Possibly best known for his portrayal of Alex DeLarge in A Clockwork Orange (1971) he began his professional life serving drinks in his parents' pub and then as a coffee salesman (the latter job providing inspiration for the movie O Lucky Man!); acting classes offered relief from his working-class existence, and eventually he secured work as an extra with the Royal Shakespeare Company. Apart from this struggle, he attended a private school in south east London called Eltham College.

McDowell made his screen debut in Poor Cow (1967) followed by The Raging Moon (1970), Figures in a Landscape (1970) and If... (1968) by British director Lindsay Anderson. His performances caught the attention of Stanley Kubrick, who cast McDowell as the lead in A Clockwork Orange. Unfortunately, despite winning great acclaim (nominated for Best Actor by the New York Film Critics Circle) for his role as the leader of a gang of futuristic toughs, the role created a characterization so unforgettable that the public had a hard time separating actor from character.

Fortunately, good parts did come his way, both on stage and screen. He rejoined Lindsay Anderson for the ambitious O Lucky Man! (1973) and Britannia Hospital (1982), and starred in Royal Flash (1975). McDowell regularly turned up on British Television productions in the early 1970s in adaptations of theatre classics. He co-starred in Voyage of the Damned (1976), and made a favourable Hollywood-movie debut as H. G. Wells in Time After Time (1979). That popular movie also introduced him to Mary Steenburgen, whom he subsequently married in 1980, but divorced ten years later in 1990.

McDowell played mainly villainous parts in the late 1970s and 1980s — none more notorious than the title character in the controversial Caligula (1979). He also appeared in the 1983 action film Blue Thunder as F.E. Cochrane, and the 1982 remake of Cat People.

He is also well known in Star Trek circles as "the man who killed Captain James T. Kirk" in the film Star Trek: Generations, in which he played the mad scientist Dr. Tolian Soran. McDowell is also the uncle of Star Trek: Deep Space Nine cast member Alexander Siddig.

In 1991, McDowell married Kelley Kuhr. He has three children, two by Steenburgen: Lily Amanda, born January 21, 1981 and Charles Malcolm born July 10, 1983. His third child, and first by Kuhr, is named Beckett Taylor and was born on January 29, 2004.

McDowell also had a part in the computer games Wing Commander III and Wing Commander IV as Admiral Geoffrey Tolwyn, co-starring next to Mark Hamill.

McDowell appeared in the short-lived 1996 - 1997 sitcom Pearl, opposite Rhea Perlman, as well as playing the part of Kesslee in 1995 film Tank Girl. He also played the role of Mr. Roarke (formely played by Ricardo Montalban) in the short lived 1998 remake of Fantasy Island.

In 2005, McDowell lent his voice talent to the album Back Against The Wall

In 2006 he was a special guest star on Law and Order: Criminal Intent as Radio Moguel Jonas Slaughter, a man who admits to killing one of his sons and manipulates the other into a dying decloration confession to save his own skin. He also appeared in Monk as an arrogant fashion photographer who committed cold blooded murder.

McDowell even contributed a cameo as himself in Robert Altman's The Player as a variation on himself by chastising protagonist Griffin Mill (Tim Robbins) for badmouthing him behind his back.