The son of an electrician and younger brother of actor Randy Quaid, Dennis was born in Houston, Texas on April 9, 1954. He began acting in high school, and in college he enrolled in a drama program. He dropped out at the age of 20 to follow his brother to Hollywood and spent the next year mired in rejection and relative unemployment. He got his first break in 1977 when he was cast in minor roles in I Never Promised You a Rose Garden and 9/30/55, but it was not until 1979, when he starred in the seminal coming-of-age drama Breaking Away, that Quaid gained attention. It was his role as astronaut Gordo Cooper in The Right Stuff four years later that finally gave the actor his Hollywood breakthrough. He subsequently went on to appear in a number of films of widely varying quality. 1987 proved to be a particularly good year for Quaid, as he did acclaimed work in The Big Easy and Suspect. That same year, he also starred in the comedy Innerspace; that experience proved to be an auspicious one, as it provided him with an introduction to co-star Meg Ryan, whom he would marry in 1991. The two also starred together in the 1988 mystery D.O.A. and in the crime drama Flesh and Bone in 1993.

Other notable roles for Quaid included that of wild man Jerry Lee Lewis in Great Balls of Fire (1989), a 1930s union organizer in Come See the Paradise (1990), and Meryl Streep's love interest in Postcards From the Edge (1990). During a large part of the '90s, Quaid starred in a string of disappointing films, including the disastrous Wyatt Earp (1994) and the failed medieval fantasy Dragonheart (1996). He made something of a comeback in 1998, appearing in the ensemble film Playing By Heart and the successful remake of The Parent Trap, in which he starred opposite Natasha Richardson. The following year, he had a starring role as a Miami football team's legendary quarterback in Oliver Stone's Any Given Sunday, and then starred in the supernatural thriller Frequency (2000) as a dead man who is able to communicate with his son (James Caviezel) over ham radio. Though both films proved moderately successful, it was two-years-later that Quaid would truly return to the good graces of critics with his striking turn in director Todd Haynes' Far From Heaven. As a closeted homosexual husband living a typical suburban dream in 1950s era Connecticut, Quaid's sensitive performance proved integral to convincingly recreating the tone of a Douglas Sirk era /melodrama.