After writing screenplays for other Italian directors, including a collaboration with Bernardo Bertolucci for Sergio Leone's "Once Upon a Time in the West" (1969), Argento made an impressive directorial debut with "The Bird with the Crystal Plummage" (1969), for which he also wrote the screenplay. About an American writer who witnesses a murder and becomes caught up in the investigation, the film is now considered a precursor to the slasher genre of the 1980s.

In "Four Flies on Grey Velvet" (1972) and "Deep Red" (1975) Argento once again used a murder mystery format to experiment with the limits of the horror genre, employing special effects and music to heighten tension. While the first two installments of a proposed trilogy "Suspiria" (1976) and "Inferno" (1980), had confusing plot devices, Argento's visual sense nonetheless managed to make the films compelling, even as the story lines became increasingly inconsequential. Once again employing a routine murder mystery plotting device in "Unsane" (1982), he used the narrative structure as a departure point for a series of visually arresting murder sequences.

Argento's first English-language feature was a European box office success under the title "Phenomena" which New Line retitled "Creepers" (1985) and edited for US release. The story of a teenager with telepathic abilities who becomes involved in the hunt for a psychotic killer, its sometimes confusing plot was supplanted by an engaging visual style which included eccentric camera angles, slow motion sequences, arresting lighting and energetic editing.

Argento joined forces with cult director George Romero on "Dawn of the Dead" (1978) in several technical capacities, and then directed "The Black Cat" segment in the episodic "Two Evil Eyes" (1990) in which Romero directed the other half, "The Facts in the Case of Mr. Valdemar". One of Argento's most baroque films ever came from this period as well, the Italian-made "Opera/Terror at the Opera" (1987). Here he explicitly drew upon Alfred Hitchcock (via "The Birds") in a technical tour de force which revamped "The Phantom of the Opera". Argento made a rare acting appearance in John Landis' "Innocent Blood" (1992) before directing his first American feature, "Trauma" (1994), a campy orgy of bloodletting which featured a hooded killer who sawed off the heads of his victims. His daughter Asia played the female lead; she was also the female lead in his 1999 remake of "The Phantom of the Opera".