Vaughan was born in Cleveland, Ohio. He graduated from St. Ignatius High School in Cleveland. As an undergraduate film student at New York University, Vaughan took part in Marvel's Stan-hattan Project, a class for fledgling comic book writers. His first credit was Cable #43 (May 1997).

Vaughan has written most of the major DC and Marvel characters, including Batman and the X-Men. He has also written several screenplays, stage plays, romance novellas, and short stories, although he prefers writing comic books. He has stated in an interview with Wizarduniverse.com that he prefers to write his own creations like The Last Man and Ex Machina.

• Eisner Award (2008) for Best Series (along with artists Pia Guerra and Jose Marzan, Jr.) for Y: The Last Man.
• Eisner Award (2005) for Best Writer, for his work on Y: The Last Man, Runaways, Ex Machina and Marvel's Ultimate X-Men, and for Best New Series (along with artists Tony Harris and Tom Feister) for Ex Machina.

• Nominated for five Eisners in 2006: Best Writer; Best Single Issue, Best Serialized Story and Best Continuing Series for Ex Machina; and Best Serialized Story for Y: The Last Man.

• "Comic's Best Writer" (2006), Wizard magazine.

• Nominated for the Hugo Award for Best Graphic Story (2009), Y: The Last Man, Volume 10: Whys and Wherefores.

Marvel Comics

• Ka-Zar Annual '97 (1997) (first Marvel Comics work)
• Cable #43 (1997)
• Tales from the Age of Apocalypse #2 (1997)
• What If #112 (1998)
• Wolverine #131 (1998)
• Captain America: Sentinel of Liberty #5, 7 (1999)
• X-Men: Unlimited #22 (1999) (Cat & Mouse story only)
• X-Men Icons: Cyclops #1-4 (2001)
• The Hood #1-6 (2002)
• X-Men Icons: Chamber #1-4 (2002-2003)
• X-Men 2 Movie Prequel: Wolverine (2003)
• Mystique #1-13 (2003-2004)
• Runaways (Vol. 1) #1-18 (2003-2004)
• 411 #2 (2003)
• Spider-Man/Doctor Octopus: Negative Exposure #1-5 (2003-2004)
• Ultimate X-Men #46-65, Annual #1 (2004-2006)
• Runaways (Vol. 2) #1-24 (2005-2007)
• Wha...Huh? #1 (2005)
• X-Men/Runaways #1 (2006)
• Dr. Strange: The Oath #1-5 (2006-2007)
• Logan #1-3 (2008)

DC Comics

• Gotham City Secret Files & Origins (back-up) (2000)
• The Titans #14 (co-writer with Devin Grayson, 2000)
• Sins of Youth: Wonder Girls #1 (2000)
• Sins of Youth: Secret Files & Origins #1 (2000)
• Young Justice #22 (2000)
• Wonder Woman vol. 2, #160-161 (2000)
• Superman Annual #12 (2000)
• Circle of Fire #1-2 (2000)
• Green Lantern and Adam Strange #1 (2000)
• Green Lantern and the Atom #1 (2000)
• JLA Annual #4 (2000)
• Batman #588-590 (2001)
• Detective Comics #787 (2003)

Vertigo Comics

• Winter's Edge #3 (2000)
• Swamp Thing (Vol. 3) #1-20 (2000-2001)
• Vertigo Secret Files & Origins: Swamp Thing #1 (2000)
• The Last Man #1-60 (2002-2008)
• Pride of Baghdad (2007)

Wildstorm Comics

• Ex Machina #1-50 (2004-2010)
• Tom Strong #28 (2004)
• Ex Machina Special Edition #1-4 (2006-2009)
• Midnighter #7 (2007)

Dark Horse Comics

• Michael Chabon Presents: The Amazing Adventures of the Escapist (anthology) #3. Entitled "To Reign in Hell." (2004)
• Michael Chabon Presents: The Amazing Adventures of the Escapist (anthology) #8. Vaughan's story was reprinted as The Escapists #1. (2005)
• The Escapists #1-6 (2006)
• Buffy the Vampire Slayer Season Eight #6-9: No Future for You arc (2007)

Television

• Lost (2006-2009)
• 3.17 - "Catch-22" — April 18, 2007 (with Jeff Pinkner)
• Missing Piece #3 (PC #101) — "King of the Castle" — November 20, 2007
• Missing Piece #5 (PC #106) — "Operation: Sleeper" — December 3, 2007
• 4.02 - "Confirmed Dead" — February 7, 2008 (with Drew Goddard)
• 4.08 - "Meet Kevin Johnson" — March 20, 2008 (with Elizabeth Sarnoff)
• 4.09 - "The Shape of Things to Come" - April 24, 2008 (with Drew Goddard)
• 5.04 - "The Little Prince" - February 4, 2009 (with Melinda Hsu Taylor)
• 5.09 - "Namaste" - March 18, 2009 (with Paul Zbyszewski)
• 5.12 - "Dead is Dead" - April 8, 2009 (with Elizabeth Sarnoff)

Films

• Y: The Last Man (screenplay)
• Ex Machina
• Runaways Marvel Studios to Adapt Runaways - Superhero Hype!
• Roundtable (screenplay)