George Pérez was born in the South Bronx, New York City, on June 9, 1954, to Jorge Guzman Pérez and Luz Maria Izquierdo, who were both from Caguas, Puerto Rico, but who did not meet until approximately 1949 or 1950, after both had settled in New Jersey while searching for job opportunities. They married in October 26, 1954 and subsequently moved to New York, where Jorge worked in the meat packing industry while Luz was a homemaker. George's younger brother David was born May 28, 1955. Both brothers aspired at a young age to be artists. with George Pérez beginning to draw at the age of five.

Pérez came to prominence with Marvel's superhero-team comic The Avengers, starting with issue #141. In the 1970s, Pérez illustrated several other Marvel titles, including Creatures on the Loose, featuring the Man-Wolf; The Inhumans; and Fantastic Four. Writer Roy Thomas and Pérez crafted a metafictional story for Fantastic Four #176 (Nov. 1976) in which the Impossible Man visited the offices of Marvel Comics and met numerous comics creators. Whilst most of Pérez' Fantastic Four issues were written by Roy Thomas or Len Wein, it would be a Fantastic Four Annual where he would have his first major collaboration with Writer Marv Wolfman. Pérez drew the first part of Writer Jim Shooter's "The Korvac Saga", which featured nearly every Avenger who joined the team up to that point. Shooter and Pérez introduced the character of Henry Peter Gyrich, the Avengers' liaison to the United States National Security Council in the second chapter of that same storyline. Writer David Michelinie and Pérez created the Taskmaster in The Avengers #195 (May 1980).

Pérez's first involvement with the professional comics industry was as Artist Rich Buckler's assistant in 1973, and made his professional debut in Marvel Comics' Astonishing Tales #25 (Aug. 1974) as penciler of an untitled two-page satire of Buckler's character Deathlok, star of that comic's main feature. Soon Pérez became a Marvel regular, penciling a run of "Sons of the Tiger", a serialized action-adventure strip published in Marvel's long-running Deadly Hands of Kung Fu magazine and authored by Bill Mantlo. He and Mantlo co-created the White Tiger (comics' first Puerto Rican superhero) a character that soon appeared in Marvel's color comics, most notably the Spider-Man titles.

Pérez won a 1979 Eagle Award (with Jim Shooter, Sal Buscema, and David Wenzel) for Best Continued Story for his work on The Avengers #167–168 and 170–177. In 1980 he won the Eagle Award for Best Comicbook Cover for Avengers #185. He won the Eagle Award for Favourite Artist (penciller) in 1986.

In 1980, while still drawing The Avengers for Marvel, Pérez began working for their rival DC Comics. Offered the art chores for the launch of The New Teen Titans, written by Wolfman, Pérez' real incentive was the opportunity to draw Justice League of America (an ambition of Pérez's which "seemed like a natural progress from the Avengers"). Long-time Justice League Artist Dick Dillin died right around that time, providing an opportunity for Pérez to step in as regular Artist. While Pérez's stint on the JLA was popular with fans, his career took off with the New Teen Titans. The New Teen Titans was launched in a special preview in DC Comics Presents #26 (October 1980). This incarnation of the Titans was intended to be DC's answer to Marvel's increasingly popular X-Men comic, and Wolfman and Pérez indeed struck gold. A New Teen Titans drug awareness comic book sponsored by the Keebler Company, and drawn by Pérez was published in cooperation with The President's Drug Awareness Campaign in 1983. In August 1984, a second series of The New Teen Titans was launched by Wolfman and Pérez. Moreover, Pérez's facility with layouts, details, and faces improved enormously during his four years on the book, making him one of the most popular artists in comics as evidenced by the numerous industry awards he would receive during this time. (See Awards section below.)

Pérez has won several Comics Buyer's Guide Fan Awards. He won the "Favorite Artist" award in 1983 and 1985 and "Favorite Penciler" in 1987. In addition, he won the "Favorite Cover Artist" award three consecutive years 1985-1987.

Pérez took a leave of absence from The New Teen Titans in 1984 to focus on his next project with Marv Wolfman, DC's 1985 50th-anniversary event, Crisis on Infinite Earths. Crisis purportedly featured every single character DC owned, in a story which radically restructured the DC universe's continuity. Pérez was inked on the series by Dick Giordano, Mike DeCarlo, and Jerry Ordway. After Crisis, Pérez inked the final issue of Superman (issue #423) in September 1986, over Curt Swan's pencils for Part 1 of the 2-part story Whatever Happened to the Man of Tomorrow? by Writer Alan Moore. The following month, Pérez was one of the artists on Batman #400 (October 1986) Wolfman and Pérez teamed again to produce the History of the DC Universe limited series to summarize the company's new history. Pérez drew the cover for the DC Heroes roleplaying game (1985) from Mayfair Games. Pérez also illustrated the cover for the fourth edition of the Champions roleplaying game (1989) from Hero Games.

Crisis on Infinite Earths won the award for "Favorite Limited Series" in 1985.

Wonder Woman was rebooted in 1987. Writer Greg Potter spent several months working with Editor Janice Race on new concepts for the character, before being joined by Pérez. Inspired by John Byrne and Frank Miller's work on refashioning Superman and Batman, Pérez came in as the plotter and penciler of Wonder Woman. The relaunch tied the character more closely to the Greek gods and jettisoned many of the extraneous elements of her history. Pérez at first worked with Potter and Len Wein on the stories, but eventually took over the full scripting chores. Later, Mindy Newell joined Pérez as co-writer for nearly a year. While not as popular as either Titans or Crisis, the series was a very successful relaunch of one of DC's flagship characters. Pérez would work on the title for five years, leaving as Artist after issue #24, but remaining as Writer up to issue #62, leaving in 1992. In 2001, Pérez returned to the character, co-writing a two-part story in issues #168-169 with writer/artist Phil Jimenez. Pérez drew the cover for Wonder Woman #600 (Aug. 2010) as well as some interior art. For the successful 2017 Wonder Woman feature film, Director Patty Jenkins would credit Pérez's work on the title character as a major influence, on par with the work of the original creator, william Moulton Marston.

Pérez returned as co-plotter/penciller of The New Teen Titans with issue #50 (Dec. 1988), the series being renamed to The New Titans. Issue #50 tells a new origin story for Wonder Girl, her link to Wonder Woman having been severed due to retcons in Crisis on Infinite Earths. Pérez remained as penciller with the book through to issue #55, 57 and 60, while only providing layouts for issues 58–59, and 61, with Artist Tom Grummett finishing pencils and Bob McLeod as inker. The "A Lonely Place of Dying" storyline crossed over with the Batman title and introduced Tim Drake as the new Robin. Pérez remained as inker for the cover art to issues #62–67 and co-plotted the stories for #66–67 before departing from the Titans series once again.

In the 1990s, Pérez left the spotlight, although he worked on several projects, including working on the Jurassic Park comic book adaptation of the movie for Topps Comics in 1993, adapted by Walt Simonson and pencilled by Gil Kane, with Pérez as inker, but most notably at Marvel Comics with Sachs and Violens and Hulk: Future Imperfect, both written by Peter David. David has named Pérez his favorite artistic collaborator, and one of the three artists whose art has mostly closely matched the visuals he conceived when writing a comic book script (the others being Leonard Kirk and Dale Keown).

Also in 1991, Pérez signed on to pencil the six-issue limited series Infinity Gauntlet for Marvel Comics, which was written by Jim Starlin. However, due to the turbulence happening concurrently with War of the Gods, this was a very stressful personal period for Pérez, and he was not able to finish penciling the entire run of Infinity Gauntlet, leaving the project part way through issue #4. The Infinity Gauntlet editorial team decided to find a replacement Artist to finish the miniseries, and Ron Lim was the Artist chosen (although Pérez offered to remain on as the inker over Lim's cover art for the remainder of the miniseries).

Pérez returned to DC Comics in October 1996 for another incarnation of the Teen Titans. Teen Titans vol. 2 was written and penciled by Dan Jurgens, with Pérez as inker for the first 15 issues of its twenty four-issue run. The series ended in September 1998.

Pérez has one creator-owned comic, the unfinished Crimson Plague. A science fiction story about an alien with ultra-toxic blood, the first issue was published in 1997 by the now defunct Event Comics. In June 2000, the original first issue was re-published by Gorilla Comics with additional material and pages, with a follow-up issue published in September 2000. Due to the extreme high costs of being a self publisher, which ended up being a financial burden and putting himself in major debt, Pérez ended Crimson Plague a second time and it is unknown if he intends to do anything else with the comic. George Pérez Storyteller includes artwork from the unpublished third issue of Crimson Plague.

He is a co-chairman of the board of the comic industry charity The Hero Initiative and serves on its Disbursement Committee. In 2005, an animated version of Pérez made a cameo appearance in the Teen Titans animated series episode titled "Go", which was an adaptation of The New Teen Titans #1. In the episode "For Real" André LeBlanc attacks a bank called "Bank of Pérez". In City of Heroes, a Massively Multiplayer Online RPG about superheroes, an entire zone within the game (Pérez Park) is named after him.

In May 2006, Pérez illustrated the cover art to one of the alternative covers to the direct market release of the annual Official Overstreet Comic Book Price Guide (36th edition) featuring Wonder Woman. He was guest Artist for an issue of JSA #82 (April 2006) and was cover Artist from issues #82–87. He drew the first ten issues of DC's The Brave and the Bold (vol. 2, 2007–2010) with Writer Mark Waid. Pérez worked on Infinite Crisis, the follow-up to Crisis on Infinite Earths, as a fill in Artist. He worked on Final Crisis: Legion of 3 Worlds in 2008-2009, thus contributing to every chapter of DC's Crisis trilogy. He is also working with Marv Wolfman on a direct-to-DVD movie adaptation of the "Judas Contract" story arc from Teen Titans, which has been scheduled for release in 2017.

In September 2011, DC launched a new Superman series written by Pérez, who also provided breakdowns and cover art, with interior art by Jesús Merino and Nicola Scott. Pérez remained until issue #6. The New Teen Titans: Games hardcover graphic novel was published the same month reuniting the creative team of Wolfman and Pérez. He was the inker of the new Green Arrow series, also launched in the same timeframe, over Artist Dan Jurgens' pencils, reuniting the mid-1990s Teen Titans art team. Pérez and Kevin Maguire were alternating artists on a Worlds' Finest revival written by Paul Levitz.

In July 2012, Pérez explained his departure from Superman as a reaction to the level of editorial oversight he experienced. This included inconsistent reasons given for rewrites of his material, the inability of editors to explain to him basic aspects of the New 52 Superman's status quo (such as whether his adoptive parents were still alive), and restrictions imposed by having to be consistent with Action Comics, which is set five years earlier than Superman, a situation complicated by the fact that Action Writer Grant Morrison was not forthcoming about his plans.

Pérez had a stint as Writer of Silver Surfer vol. 2 #111–123 (December 1995 – December 1996). He would also write the crossover special Silver Surfer/Superman in 1996. Pérez finally returned to a major ongoing title for the third series of The Avengers, written by Kurt Busiek, where he remained for nearly three years, again receiving critical and fan acclaim for his polished and dynamic art. After leaving the series, he and Busiek produced the long-awaited JLA/Avengers inter-company crossover, which saw print in late 2003. A JLA/Avengers crossover was to have been published in the 1980s, but differences between DC and Marvel forced the comic to be canceled. As the Artist on the story, Pérez had drawn approximately 21 pages of the original crossover, which were not published until the 2004 hardcover edition of JLA/Avengers: The Collector's Edition.

From September 2014 to December 2016, Pérez wrote and drew six issues of his own creation Sirens, published by BOOM! Studios. It is a science fiction miniseries dedicated to a group of women with extraordinary powers, who fight against evil across time and space.

Pérez is married to Carol Flynn. He has no children but has a niece and nephew from his brother David. He is diabetic, and has undergone surgery for diabetic retinopathy. In May 2017, Pérez was admitted to a hospital with chest pains and was diagnosed as having had a heart attack while travelling to New Jersey for a convention. He was subsequently released from the hospital after having a coronary stent fitted.