| Guest star | Played as |
|---|---|
| "Weird Al" Yankovic | Himself |
| Kathie Lee Gifford | Herself |
| Kevin Michael Richardson | Security guard |
| Michael York | Mason Fairbanks |
| 50 Cent | Himself |
| Adam West | Himself, Batman |
| Aerosmith | Themselves |
| Alan Moore | Himself |
| Albert Brooks | Hank Scorpio, Brad Goodman, Tab Spangler, Jacques,Russ Cargill |
| Alec Baldwin | Himself, Caleb Thorn |
| Alex Rocco | Roger Meyers, Jr. |
| Alex Trebek | Himself |
| Amy Poehler | Jenda |
| Amy Tan | Herself |
| Andre Agassi | Himself |
| Andrea Martin | Apu's mother |
| Andy Dick | Himself |
| Andy Serkis | Cleanie |
| Angela Bassett | Michelle Obama |
| Anne Bancroft | Dr. Zweig |
| Anne Hathaway | Princess Penelope, Jenny |
| Antonio Fargas | Huggy Bear |
| Art Spiegelman | Himself |
| Ashley Olsen | Herself |
| Audrey Meadows | Bea Simmons |
| Baha Men | Sing "Who Wants a Haircut?", Themselves |
| Barry White | Himself |
| Ben Stiller | Garth Motherloving |
| Bette Midler | Herself |
| Beverly D'Angelo | Lurleen Lumpkin |
| Bill Saluga | Ray J. Johnson |
| Blink-182 | Themselves |
| Bob Costas | Himself |
| Bob Denver | Himself |
| Bob Hope | Himself |
| Bob Newhart | Himself |
| Bobcat Goldthwait | Himself |
| Brave Combo | Play the end credits |
| Brendan Fraser | Brad |
| Bret Hart | Himself |
| Brian Grazer | Himself |
| Britney Spears | Herself |
| Brooke Shields | Herself |
| Bruce Baum | Himself |
| Bruce Vilanch | Himself |
| Burt Ward | Robin |
| Butch Patrick | Himself |
| Buzz Aldrin | Himself |
| C.F. Turner | Himself |
| Carmen Electra | Herself |
| Charles Napier | Grant Conor, Officer Krackney, Warden |
| Charlie Rose | Himself |
| Chick Hearn | Announcer |
| Chris Martin | Himself |
| Christina Ricci | Erin |
| Christopher Guest | Nigel Tufnel |
| Chuck Liddell | Himself |
| Clarence Clemons | Narrator |
| Cloris Leachman | Mrs. Glick |
| Colm Meaney | Tom O'Flanagan |
| Conan O'Brien | Himself |
| Cooper Manning | Himself |
| Cyndi Lauper | Herself |
| Cypress Hill | Themselves |
| Dan Marino | Himself |
| Dan Rather | Himself |
| Daniel Clowes | Himself |
| Daniel Stern | Narrator |
| Danny DeVito | Herbert Powell |
| Darryl Strawberry | Himself |
| Daryl L. Coley | Bleeding Gums Murphy |
| Dave Thomas | Rex Banner, Bob Hope |
| David Byrne | Himself |
| David Crosby | Himself |
| David Duchovny | Fox Mulder |
| David Hyde Pierce | Cecil Terwilliger, Man in the crowd |
| David Lander | Squiggy |
| Delroy Lindo | Gabriel |
| Denice Kumagai | Dancer, Mother |
| Denis Leary | Himself |
| Dennis Franz | Himself playing Homer |
| Dennis Rodman | Himself |
| Dennis Weaver | Buck McCoy |
| Diane Tanaka | Hostess |
| Dick Cavett | Himself |
| Dick Clark | Himself |
| Dick Tufeld | Lost in Space robot |
| Diedrich Bader | Sheriff |
| Dixie Chicks | Themselves |
| Dolly Parton | Herself |
| Don Cheadle | Brother Faith |
| Don Mattingly | Himself |
| Donald Sutherland | Hollis Hurlbut |
| Dr. Demento | Himself |
| Drew Barrymore | Sophie |
| Drew Carey | Himself |
| Dudley R. Herschbach | Himself |
| Dustin Hoffman | Mr. Bergstrom |
| Eartha Kitt | Herself |
| Ed Begley, Jr. | Himself |
| Ed McMahon | Himself |
| Eddie Izzard | Queen Elizabeth II |
| Edward Asner | Newspaper editor |
| Edward Norton | Devon Bradley |
| Eli Manning | Himself |
| Elizabeth Taylor | Maggie Simpson, Herself |
| Ellen Page | Alaska Nebraska |
| Elliott Gould | Himself |
| Elton John | Himself |
| Elvis Costello | Himself |
| Elvis Stojko | Himself |
| Elwood Edwards | Virtual doctor |
| Emily Blunt | Juliet |
| Eric Idle | Declan Desmond |
| Ernest Borgnine | Himself |
| Evan Marriott | Himself |
| Fall Out Boy | Play the end credits |
| Fantasia Barrino | Clarissa Wellington |
| Fran Drescher | Female Golem |
| Frances McDormand | Melanie Upfoot |
| Frances Sternhagen | Mrs. Bellamy |
| Frank Gehry | Himself |
| Frank Welker | Santa's Little Helper, Additional dog voices, Various animals, Executive Vice President dog, Laddie, Badger, Dog, Werewolf Flanders, Baboons, Lion, Stampy, Gremlin, Parrot, Princess |
| Frankie Muniz | Thelonius |
| Fred Willard | Wally Kogen |
| Fyvush Finkel | Himself playing Krusty |
| Gailard Sartain | Charles "Big" Daddy |
| Garry Marshall | Larry Kidkill |
| Gary Busey | Himself |
| Gary Coleman | Himself |
| Gary Larson | Himself |
| Gedde Watanabe | Waiter, Father, Toilet, Factory foreman |
| Gene Tenace | Himself |
| George W Bush | Himself |
| George Carlin | Munchie |
| George Fenneman | Narrator |
| George Harrison | Himself |
| George Plimpton | Himself |
| George Takei | Waiter, Wink, Akira |
| George Wendt | Norm Peterson |
| Gerry Cooney | Himself |
| Gillian Anderson | Dana Scully |
| Glen Hansard | Street musician |
| Glenn Close | Mona Simpson |
| Gore Vidal | Himself |
| Green Day | Themselves |
| Greg Berg | Rory |
| Hank Williams, Jr. | Sings "Canyonero!" |
| Harry Morgan | Bill Gannon |
| Harvey Fierstein | Karl |
| Helen Fielding | Herself |
| Helen Hunt | Renee |
| Henry Corden | Fred Flintstone |
| Henry Winkler | Ramrod |
| Huell Howser | Himself |
| Hugh Hefner | Himself |
| Ian McKellen | Himself |
| Isabel Sanford | Herself |
| Isabella Rossellini | Astrid Weller |
| J. K. Rowling | Herself |
| J. K. Simmons | Tabloid editor, J. Jonah Jameson |
| Jack Black | Milo |
| Jack Burns | Edward Christian |
| Jack LaLanne | Himself |
| Jack Lemmon | Frank Ormand |
| Jack Ong | Fisherman |
| Jack Sheldon | Amendment |
| Jackie Mason | Rabbi Krustofski |
| Jackson Browne | Himself |
| James Brown | Himself |
| James Caan | Himself |
| James Earl Jones | Removal man, Serak the Preparer, Narrator, Alternate universe Maggie |
| James L. Brooks | Himself |
| James Lipton | Himself |
| James Patterson | Himself |
| James Taylor | Himself |
| James Woods | Himself |
| Jan Hooks | Manjula Nahasapeemapetilon |
| Jane Kaczmarek | Judge Constance Harm |
| Jane Leeves | Edwina |
| Janeane Garofalo | Herself |
| Jason Bateman | Himself |
| Jasper Johns | Himself |
| Jay Leno | Himself |
| Jay Mohr | Christopher Walken |
| Jay North | Himself |
| Jeff Bezos | Himself |
| Jeff Goldblum | MacArthur Park |
| Jennifer Garner | Herself |
| Jerry Lewis | Professor John Frink Sr. |
| Jerry Springer | Himself |
| Jim Cummings | Duncan |
| Jim Forbes | Narrator |
| Jim Jarmusch | Himself |
| Jim Lau | Hong Kong doctor |
| Jim Varney | Cooter |
| Joan Kenley | Telephone voice |
| Jodie Foster | Maggie Simpson |
| Joe C. | Himself |
| Joe Frazier | Himself |
| Joe Mantegna | Fat Tony |
| Joe Montana | Himself |
| Joe Namath | Himself |
| Joe Pantoliano | Dante Calabresis |
| Joey Miyashima | Toshiro |
| John C. Reilly | Himself |
| John DiMaggio | Bender |
| John Goodman | Meathook |
| John Madden | Himself |
| John Mahoney | Dr. Robert Terwilliger, Sr. |
| John Ratzenberger | Cliff Clavin |
| John Updike | Himself |
| John Waters | John |
| Johnny Carson | Himself |
| Johnny Cash | Coyote |
| Johnny Kassir | Possum |
| Johnny Unitas | Himself |
| Jon Lovitz | Artie Ziff, Jay Sherman, Llewelyn Sinclair, Aristotle Amadopoulis, Professor Lombardo, Enrico Irriazio |
| Jon Stewart | Himself |
| Jonah Hill | Andy Hamilton |
| Jonathan Franzen | Himself |
| Jonathan Taylor Thomas | Luke Stetson |
| Jordan Nagai | Charlie |
| José Canseco | Himself |
| Joshua Jackson | Jesse Grass |
| Joyce Brothers | Herself |
| Judith Owen | Herself |
| Julia Louis-Dreyfus | Gloria |
| June Foray | Babysitter service receptionist |
| Karen Maruyama | Dancer, Stewardess |
| Kathleen Turner | Stacy Lovell |
| Kathy Griffin | Francine |
| Keith Olbermann | Himself |
| Keith Richards | Himself |
| Kelsey Grammer | Sideshow Bob |
| Ken Griffey, Jr. | Himself |
| Ken Levine | Dan Horde |
| Keone Young | Sumo wrestler |
| Kevin Michael Richardson | Prisoner |
| Kid Rock | Himself |
| Kiefer Sutherland | Jack Bauer, Colonel |
| Kim Basinger | Herself |
| Kim Cattrall | Chloe Talbot, Fourth Simpson child |
| Kimmy Robertson | Samantha Stanky |
| Kipp Lennon | Leon Kompowsky's singing voice |
| Kirk Douglas | Chester J. Lampwick |
| Kurt Loder | Himself |
| Lance Armstrong | Himself |
| Larry Hagman | Wallace Brady |
| Larry Holmes | Himself |
| Larry King | Himself |
| Lawrence Tierney | Don Brodka |
| LeBron James | Himself |
| Leeza Gibbons | Herself |
| Lenny Kravitz | Himself |
| Leonard Nimoy | Himself |
| Liam Neeson | Father Sean |
| Lily Tomlin | Tammy |
| Linda McCartney | Herself |
| Linda Ronstadt | Herself |
| Lionel Richie | Himself |
| Lisa Kudrow | Alex Whitney |
| Lisa Leslie | Herself |
| Little Richard | Himself |
| Los Lobos | Play end credits |
| Lucy Lawless | Herself |
| Lucy Liu | Madam Wu |
| Ludacris | Himself |
| Luke Perry | Himself |
| Magic Johnson | Himself |
| Mandy Moore | Tabitha Vixx |
| Mandy Patinkin | Hugh Parkfield |
| Marc Wilmore | Dr. Wilmore |
| Maria Grazia Cucinotta | Francessa |
| Marisa Tomei | Sara Sloane |
| Mark Cuban | Himself |
| Mark Hamill | Himself, Leavelle |
| Mark McGwire | Himself |
| Markéta Irglová | Eastern European woman |
| Martin Mull | Seth |
| Martin Sheen | The real Seymour Skinner |
| Marv Albert | Himself |
| Mary Lynn Rajskub | Chloe O'Brian |
| Mary-Kate Olsen | Herself |
| Matt Dillon | Louie |
| Matt Groening | Himself |
| Matthew Perry | Ultrahouse's Matthew Perry voice |
| Maurice LaMarche | Additional voice, Commander McBragg, Orson Welles, Billy, Horn stuffer, Fox announcer, Government official, Jock, Toucan Sam, Robert D. Eisenhower, George C. Scott, Inspector |
| Maya Rudolph | Julia |
| Meg Ryan | Dr. Stacy Swanson |
| Mel Brooks | Himself |
| Mel Gibson | Himself |
| Melanie Griffith | Herself |
| Merl Reagle | Himself |
| Meryl Streep | Jessica Lovejoy |
| Metallica | Themselves |
| Michael Buffer | Himself |
| Michael Chabon | Himself |
| Michael Imperioli | Dante Calabresis Jr. |
| Michael Jackson | Leon Kompowsky |
| Michael Keaton | Jack Crowley |
| Michael McKean | Jerry Rude, David St. Hubbins |
| Michael Moore | Himself |
| Michelle Kwan | Herself |
| Michelle Pfeiffer | Mindy Simmons |
| Mick Jagger | Himself |
| Mickey Rooney | Himself |
| Mike Judge | Hank Hill |
| Mike Scioscia | Himself |
| Mitch Albom | Himself |
| Mr. T | Himself |
| 'N Sync | Themselves |
| Nancy O'Dell | Herself |
| Natalie Portman | Darcy |
| Neil Patrick Harris | Himself playing Bart Simpson |
| Neve Campbell | Cassandra |
| Nichelle Nichols | Herself |
| Nick Bakay | Salem Saberhagen |
| NRBQ | Sing "You'll Never Stop The Simpsons", Perform various songs, Sing "Can't Buy Me Love" |
| Olympia Dukakis | Zelda |
| Oscar De La Hoya | Himself |
| Ozzie Smith | Himself |
| Pamela Reed | Ruth Powers |
| Parker Posey | Becky |
| Pat O'Brien | Himself |
| Pat Summerall | Himself |
| Patrick McGoohan | The Prisoner Number Six |
| Patrick Stewart | Number One |
| Paul Anka | Himself |
| Paul McCartney | Himself |
| Paul McGuinness | Himself |
| Paul Newman | Himself |
| Paul Willson | Florist |
| Paul Winfield | Lucius Sweet |
| Paul Winfield | Lucius Sweet |
| Penn Jillette | Himself |
| Penny Marshall | Ms. Lucille Botz |
| Pete Sampras | Himself |
| Peter Bogdanovich | Psychologist |
| Peter Frampton | Himself |
| Peyton Manning | Himself |
| Phil Hartman | Troy McClure, Lionel Hutz, Plato, Smooth Jimmy Apollo, Cable guy, Moses, Horst, Stockbroker, Hospital chairman, Bill Clinton, Mr. Muntz, Lyle Lanley, Charlton Heston, Evan Conover, Heaven |
| Phil McGraw | Himself |
| Philip Rosenthal | TV Dad |
| Phish | Themselves |
| Pierce Brosnan | Ultrahouse's Pierce Brosnan voice |
| Plácido Domingo | Himself |
| R. Lee Ermey | Colonel Leslie Hapablap |
| R.E.M. | Themselves |
| Randy Bachman | Himself |
| Randy Johnson | Himself |
| Ray Ramano | Ray Magini |
| Red Hot Chili Peppers | Themselves |
| Reese Witherspoon | Greta Wolfcastle |
| Regis Philbin | Himself |
| Rhea Perlman | Carla Tortelli |
| Richard Dean Anderson | Himself |
| Richard Gere | Himself |
| Richard Lewis | Male Golem |
| Ricky Gervais | Charles |
| Ringo Starr | Himself |
| Rob Reiner | Himself |
| Robert Englund | Freddy Krueger |
| Robert Evans | Himself |
| Robert Forster | Lucky Jim |
| Robert Goulet | Himself |
| Robert Pinsky | Himself |
| Robert Schimmel | Convict |
| Robert Wagner | Himself |
| Rod Steiger | Captain Tenille |
| Rodney Dangerfield | Larry Burns |
| Ron Howard | Himself |
| Ron Taylor | Bleeding Gums Murphy |
| Ronaldo | Himself |
| Rosey Grier | Himself |
| Roy Fireston | Himself |
| Rudy Giuliani | Himself |
| Rupert Murdoch | Himself |
| Sab Shimono | Mr. Sparkle, Factory worker, Japanese fisherman, Master Sushi Chef |
| Sacha Baron Cohen | Jakob |
| Sal Bando | Himself |
| Sally Stevens | Sings "Scorpio" |
| Sam McMurray | Gulliver Dark |
| Sam Neill | Molloy |
| Sara Gilbert | Laura Powers |
| Sarah Michelle Gellar | Gina Vendetti |
| Sarah Silverman | Nikki |
| Scott Thompson | Grady |
| Serena Williams | Herself |
| Seth Rogen | Lyle McCarthy |
| Shawn Colvin | Rachel Jordan |
| Shohreh Aghdashloo | Mina |
| Simon Cowell | Henry |
| Sir Mix-a-Lot | Sings "Baby Likes Fat" |
| Smothers Brothers | Themselves |
| Sonic Youth | Themselves |
| Stacy Keach | Howard K. Duff VII, Howard K. Duff VIII |
| Stan Lee | Himself |
| Stephen Colbert | Colby Kraus |
| Stephen Hawking | Himself |
| Stephen Jay Gould | Himself |
| Stephen King | Himself |
| Stephen Sondheim | Himself |
| Steve Allen | Electronically altered voice of Bart, Himself |
| Steve Buscemi | Himself, Dwight David Diddlehoffer |
| Steve Martin | Ray Patterson |
| Steve Sax | Himself |
| Steven Weber | Neil |
| Steven Wright | Himself |
| Sting | Himself |
| Susan Sarandon | Ballet teacher, Herself |
| Susie Smith | Herself |
| Suzanne Somers | Herself |
| Ted Danson | Sam Malone |
| Ted Nugent | Himself |
| Teller | Himself |
| Terry Bradshaw | Himself |
| Terry Cashman | Sings "Talkin' Softball" |
| Terry Gross | Herself |
| The B-52's | Sing "Glove Slap" |
| The Dapper Dans | The singing voices of the Be Sharps |
| The Moody Blues | Themselves |
| The Ramones | Themselves |
| The Rolling Stones | Themselves |
| The Smashing Pumpkins | Themselves |
| The White Stripes | Themselves |
| The Who | Themselves |
| Thomas Pynchon | Himself |
| Tim Conway | Himself |
| Tim Robbins | Jim Hope |
| Tito Puente | Himself |
| Tom Arnold | Himself |
| Tom Brady | Himself |
| Tom Clancy | Himself |
| Tom Hanks | Himself |
| Tom Jones | Himself |
| Tom Kite | Himself |
| Tom Petty | Himself |
| Tom Poston | Capitol City Goofball |
| Tom Savini | Himself |
| Tom Wolfe | Himself |
| Tony Bennett | Himself |
| Tony Blair | Himself |
| Tony Hawk | Himself |
| Topher Grace | Donny |
| Tracey Ullman | Emily Winthropp |
| Trevor Denman | Track announcer |
| Troy Aikman | Himself |
| U2 | Themselves |
| Venus Williams | Herself |
| Wade Boggs | Himself |
| Warren Sapp | Himself |
| Werner Klemperer | Colonel Klink |
| Will Shortz | Himself |
| Willem Dafoe | The Commandant |
| William Daniels | K.I.T.T. |
| William H. Macy | Himself |
| Willie Nelson | Himself |
| Winona Ryder | Allison Taylor |
| Wolfgang Puck | Himself |
| Woody Harrelson | Woody Boyd |
| Wren T. Brown | Virgil |
| Yael Naim | Doreet |
| Yao Ming | Himself |
| Yo La Tengo | Play end credits |
| Zooey Deschanel | Mary |