Busiek was born in Boston, Massachusetts. He grew up in various towns in the Boston area, including Lexington, where he befriended future comic book creator Scott McCloud. Busiek did not read comics as a youngster, as his parents disapproved of them. He began to read them regularly around the age of 14, when he picked up a copy of Daredevil #120 (April 1975). This was the first part of a continuity-heavy four-part story arc; Busiek was drawn to the copious history and cross-connections with other series. Throughout high school and college, he and McCloud practiced making comics.
During this time, Busiek had many letters published in comic book letter columns, and originated the theory that the Phoenix was a separate being who had impersonated Jean Grey, and that therefore Grey had not died — a premise which made its way from freelancer to freelancer, and which was eventually used in the comics. Busiek explains, "A couple of years later, after I’d broken in, I attended my first convention as a pro, in Ithaca, New York, and I stayed at Roger Stern's house. And we were talking about how much we liked the new X-Men, and he said, 'It's just a pity there's no way to bring Jean Grey back,' and I said, 'Sure there's a way, there's always a way.'"
During the last semester of his senior year, Busiek submitted some sample scripts to editor Dick Giordano at DC Comics. None of them sold, but they did get him invitations to pitch other material to DC editors, which led to his first professional work, a back-up story in Green Lantern #162 (March 1983). After writing four fill-in issues of Power Man and Iron Fist, he was given the series as his first regular assignment. Busiek was a fan of the work his predecessor, Mary Jo Duffy, had done on Power Man and Iron Fist, and emulated her lighthearted, humorous approach, not knowing that the editorial staff disapproved of this approach and had taken Duffy off the series because of it. He was fired from the series for the same reasons as Duffy, after only six issues as its regular writer. In 1985, he wrote a Red Tornado limited series.
In 1993, Busiek and artist Alex Ross produced the Marvels limited series which, as comics historian Matthew K. Manning notes, "reinvigorated painted comics as a genre, went on to become an acclaimed masterpiece, and spawned more than its own fair share of imitators." Busiek and Pat Olliffe crafted the Untold Tales of Spider-Man series beginning in September 1995. He created the Thunderbolts, a group of super-villains disguised as super-heroes, with the final page of the first issue of the series revealing that the Thunderbolts were actually the Masters of Evil, a surprise twist carefully guarded by Marvel. In February 1998, Busiek launched The Avengers vol. 3 with penciler George Pérez and Iron Man vol. 3 with artist Sean Chen. Busiek and Carlos Pacheco collaborated on the Avengers Forever limited series in 1998–1999. This replaced the Avengers: World in Chains series which the two had previously planned to work on. Busiek continued as writer of The Avengers through 2002, collaborating with artists such as Alan Davis and Kieron Dwyer. His tenure culminated with the "Kang Dynasty" storyline. In 2003, Busiek re-teamed with Pérez to create the JLA/Avengers limited series.
Busiek has worked on a number of different titles in his career, including Arrowsmith, The Liberty Project, The Power Company, Shockrockets, Superman: Secret Identity, JLA, and the award-winning Kurt Busiek's Astro City. In the 1990s, work on some of Busiek's more challenging, less mainstream projects, most notably Astro City, was repeatedly delayed by health problems brought about by mercury poisoning.
In 2004, Busiek began a new Conan series for Dark Horse Comics. In December 2005, he signed a two-year exclusive contract with DC Comics. During DC's Infinite Crisis event, he teamed with Geoff Johns on a "One Year Later" eight-part story arc titled "Up, Up and Away!" that encompassed both Superman titles. In addition, he began writing the DC title Aquaman: Sword of Atlantis from issues #40–49. Busiek became the sole writer of the Superman series with issue #654 (Sept. 2006) and Carlos Pacheco became the series' artist. Busiek and Pacheco developed an extended storyine featuring Arion coming into conflict with Superman. The plotline concluded in Superman Annual #13. Busiek wrote a 52-issue weekly DC miniseries titled Trinity, starring Batman, Superman and Wonder Woman. Each issue except for the first featured a 12-page main story by Busiek, with art by Mark Bagley, and a ten-page backup story co-written by Busiek and Fabian Nicieza, with art from various artists, including Tom Derenick, Mike Norton and Scott McDaniel.
Busiek teamed with Alex Ross on Dynamite Entertainment's Kirby: Genesis, an eight-issue miniseries which debuted in 2011. The series, which was their first full collaboration since Marvels 17 years previous, featured a large group of Jack Kirby's creator-owned characters, the rights to which were acquired by Dynamite, such as Silver Star, Captain Victory, Galaxy Green, Tiger 21 and the Ninth Men. Ross co-plotted, handled designs, and oversaw the series overall with Busiek, who scripted the story.
In June 2013, Busiek relaunched his Astro City series as part of DC's Vertigo line. Busiek commented that "Astro City's always been aimed at a more sophisticated reader, which I think suits Vertigo. Plus our backlist sales are closer to a Vertigo pattern than DCU."
Busiek is married to Ann Busiek. Both Kurt and Ann Busiek were rendered by Alex Ross as New Yorkers who react to the invasion of Silver Surfer and Galactus on page 17 of Marvels #3. Kurt is later used as the model for a wandering drunk on page 33 of the same issue.
Busiek's work has won him numerous awards in the comics industry, including the Harvey Award for Best Writer in 1998 and the Eisner Award for Best Writer in 1999. In 1994, with Marvels, he won Best Finite Series/Limited Series Eisner Award and the Best Continuing or Limited Series Harvey Award; as well as the Harvey Award for Best Single Issue or Story (for Marvels #4) in 1995. In 1996, with Astro City, Busiek won both the Eisner and Harvey awards for Best New Series. He won the Best Single Issue/Single Story Eisner three years in a row from 1996–1998 for Astro City, and for Conan: The Legend #0 in 2004. Busiek won the Best Continuing Series Eisner Award in 1997–1998, as well as the Best Serialized Story award in 1998. In addition, Astro City was awarded the 1996 Best Single Issue or Story Harvey Award, and the 1998 Harvey Award for Best Continuing or Limited Series.
Busiek was given the 1998 and 1999 Comics Buyer's Guide Awards for Favorite Writer, with additional nominations in 1997 and every year from 2000 to 2004.