Fulci was born in Rome on 17 June 1927. After studying Medicine in college and being employed for a time as an art critic, he opted for a film career, first as a Screenwriter working initially in the Italian comedy field, then later as a Director beginning with I Ladri in 1959. In the early 1960s, Fulci wrote or directed around 18 Italian comedies, many of them starring the famous Italian Comedian team of Franco Franchi and Ciccio Ingrassia.

Most of these early films did not enjoy wider distribution in English-speaking countries, and are generally not available in English. Fulci's first film distributed theatrically in the USA was Oh! Those Most Secret Agents! in 1965. Only four of his other 1960s films were released in the U.S.: Massacre Time (as The Brute and the Beast in 1968), The Man Who Killed Billy the Kid (as I'll Kill Him and Return Alone in 1968), Una sull'altra (as One on Top of the Other in 1973) and Beatrice Cenci (as Conspiracy of Torture, in 1976).

In the last decade of his life, Fulci suffered from emotional and physical health problems, reflected by a marked decline in the quality of his work. His wife's suicide in 1969 always weighed heavily on him (his wife Marina had killed herself with a gas oven after learning she had inoperable cancer). People who knew him spoke of a 3rd daughter he had once had who he said was killed in a car accident in the 1970s, but this story was never confirmed. Fulci suffered during the late 1980s from severe problems with his feet, which were caused by diabetes. He hid the severity of his illness from his friends and associates, so that he would not be deemed unemployable.

Fulci and Screenwriter Dardano Sacchetti share many screen credits from 1977 to 1983. Indeed, most of Fulci's most celebrated horror films were written by Sacchetti. After collaborating with Sacchetti for six years, Fulci went off on his own in 1983 to direct Conquest in Mexico, failing to involve Sacchetti in the deal. The film was supposed to be a high budget production, and Sacchetti allegedly resented the fact that Fulci had not thought to involve him in the project. The film actually wound up doing quite poorly upon its release, and afterwards, Fulci had trouble jump-starting his working relationship with Sacchetti, who by this time had gone his own way.

Several of Fulci's movies were prohibited in Europe or were released in heavily cut versions. Of the original 72 films on the infamous video nasty list in the United Kingdom, three belonged to Fulci: Zombi 2 (1979), The Beyond (1981), and House by the Cemetery (1981). After viewing Fulci's The New York Ripper, not only did the British Board of Film Classification refuse the film a certificate, but every single print in the country was taken to an airport and returned to Italy by order of James Ferman; it was not until later that VIPCO allowed the release of the film, initially outsourcing production to a foreign source under police supervision before releasing a VHS in 2002 and a DVD in 2007.

After collaborating with Screenwriter Sacchetti for six years, Fulci went off on his own in 1983 to direct the movie Conquest (a Conan-like barbarian fantasy) in Mexico, failing to involve Sacchetti in the deal. The film did poorly upon its release, and afterwards, Fulci had trouble jump-starting his working relationship with Sacchetti, who by that time had gone his own way.

Fulci became ill from hepatitis in 1984, right after he finished directing Murder Rock in New York City, and had to be hospitalized in Italy for many months. Fulci spent most of 1984 hospitalized with cirrhosis, and much of 1985 recuperating at home. After 1986, with his diabetes plaguing him and the departure of Screenwriter Dardano Sacchetti from Fulci's circle of friends, Fulci's endeavors as a Director suffered.

In 1987, Fulci accused Sacchetti of stealing a story idea of his, a project which they were planning to do together in 1983 after Fulci returned from Mexico. He claimed that Sacchetti later allowed Director Lamberto Bava to direct the project (under the title Per Sempre / Until Death) in 1987 without Fulci's knowledge that the film was even being made. Luca M. Palmerini and Gaetano Mistretta's book Spaghetti Nightmares, publishes two full interviews, one with Fulci and one with Sacchetti, explaining the reasons for the fallout.

In 1988, he had directed about two-thirds of Zombi 3 in the Philippines before having to return abruptly to Italy due to a second bout of hepatitis. The film was finished by an un-credited Bruno Mattei. Fulci later said that he hated the finished product and tried unsuccessfully to get his name removed from the credits. Mattei has said in interviews that the film was Fulci's, and that he (Mattei) just added a few extra scenes to pad out the running time.

In 1989, Fulci was hired to direct a pair of made-for-TV horror movies for the Italian market, neither of which aired in Italy due to the high amount of gore and violence. They were released later on DVD, however, outside of Italy. Fulci's intended comeback films Demonia and A Cat in the Brain were produced in 1990. Both films struggled to see release and were considered critical disappointments. His final project, the 1991 psychological thriller The Door to Silence, based on one of his short stories, also received poor reviews. The release of this film is seen by some as the critical lowest point of his career.

Fulci and Argento met in 1994 and agreed to collaborate on a horror film called The Wax Mask, a remake of the 1953 Vincent Price horror classic House of Wax, also based on a story called "The Waxwork Museum" by Gaston Leroux. Argento claimed he had heard about Fulci's miserable circumstances at the time and wanted to offer him a chance at a comeback. It is said that Argento was shocked at how thin and sickly Fulci appeared at their meeting at the 1994 Rome Fanta Festival, and said he felt very sorry for him.

Fulci made an appearance at the January 1996 Fangoria Horror Convention in New York City, two months before his death. Walking on crutches with a bandaged foot, he told attendees that he had had no idea his films were so popular outside of his native Italy, as hordes of starstruck gore fans braved blizzard conditions that weekend to meet him.

Fulci's films had remained generally ignored or dismissed for many years by the mainstream critics, who regarded his work as exploitation. However, genre fans appreciated his films as being stylish exercises in extreme gore. At least one of his films, The Beyond, has "amassed a large and dedicated following". In 1998, The Beyond was re-released to theaters by Quentin Tarantino, who has often cited the film, and Fulci himself, as a major source of inspiration. Fulci's earlier, lesser-known giallo Don't Torture a Duckling (1972) received some critical acclaim as well. Fulci regarded two of his films, Don't Torture a Duckling and Beatrice Cenci, as his best work (the latter which he said his wife had liked the best of all his films), and considered both Zombi 2 and The Beyond as the two films that forever catapulted him to cult film stardom. His daughter Camilla Fulci served as an assistant Director on his last five films (from 1989-1991) and has gone on to become an assistant Director in the Italian film industry.