He was born and raised in New York City, and attended Pittsburgh's Carnegie Mellon University. After quitting university, he began shooting mostly short films and commercials. He and friends formed Image Ten Productions in the late 1960s, and they chipped in roughly $10,000 apiece to produce what became one of the most celebrated horror films of all time: Night of the Living Dead (1968). The movie, directed by Romero and co-written with John A. Russo, became a cult classic in the 1970s. Romero updated his original screenplay and was executive producer of the remake of Night of the Living Dead directed by Tom Savini for Columbia/Tristar in 1990.

Romero's next films were less popular: There's Always Vanilla (1971), Jack's Wife/Season of the Witch (1972) and The Crazies (1973). Though not as acclaimed as Night of the Living Dead or some of his later work, these films had his signature social commentary while dealing with issues (usually horror-related) at the microscopic level. The Crazies, about a biospill that creates madness, and the critically acclaimed and arthouse success Martin (1976), a film that strikingly deconstructs the vampire myth, were the two standout efforts during this period. Like almost all of his films, they were shot in or around Romero's favorite city of Pittsburgh.

In 1978, Romero returned to the zombie genre with Dawn of the Dead (1978). Shot on a budget of just $1.5 million, the film earned over $55 million worldwide and was named one of the top cult films by Entertainment Weekly in 2003. Romero made a third entry in his "Dead Series" with Day of the Dead (1985), although this was less popular at the box office.

During this time, Romero also made Knightriders (1981), another festival favorite about a group of modern-day jousters who re-enact tournaments on motorcycles, and the successful Creepshow (1982), written by Stephen King, an anthology of tongue-in-cheek tales that were modeled after 1950s horror comics.

Throughout the latter half of the 1980s and 90s, Romero made various films, including Monkey Shines (1988) about a killer monkey; Two Evil Eyes (1990), an Edgar Allan Poe adaptation in collaboration with Dario Argento; the Stephen King adaptation The Dark Half (1992); and Bruiser (2000), about a man whose face becomes a blank mask.

Romero had a cameo appearance in Jonathan Demme's Academy Award-winning The Silence of the Lambs in 1991 as one of Hannibal Lecter's jailers.

Universal Studios produced and released a remake of Dawn of the Dead in 2004, in which Romero was not involved (though he expressed admiration for the Zack Snyder film in a graphic novel adaptation of the remake). Later that year, Romero kicked off the DC Comics title Toe Tags with a six-issue miniseries titled The Death of Death. Based on an unused script that Romero had previously written as a sequel to his "Dead Trilogy", the comic miniseries concerns Damien, an intelligent zombie who remembers his former life, struggling to find his identity as he battles armies of both the living and the dead. Typical of a Romero zombie tale, the miniseries includes ample supply of both gore and social commentary (dealing particularly here with corporate greed and terrorism - ideas he would also explore in his next film in the series, Land of the Dead). Romero has stated that the miniseries takes place in the same world as his "Dead" films, only emphasising other places in the world besides Pittsburgh, where the majority of his films take place (link).

Romero, who still lives in Pittsburgh, recently completed a fourth "Dead" movie, Land of the Dead (formerly known as Dead Reckoning), in Toronto, Ontario, with a $16 million production budget (the highest in Romero's career). Actors Dennis Hopper, Asia Argento and John Leguizamo star in the film. It was released on June 24, 2005.

Some critics have seen social commentary in much of Romero's work. They view Night of the Living Dead as a film made as a reaction to the turbulent 1960s, Dawn of the Dead as a satire on consumerism, Day of the Dead as a study of the conflict between science and the military, and Land of the Dead as an examination of class conflict.