His career began as a teenager, working as a mailboy at 20th Century Fox. He starred in Schlock (1976), which he also wrote and directed, and also directed The Kentucky Fried Movie (1977) and National Lampoon's Animal House (1978). In 1980, Landis directed Blues Brothers (which he wrote with Dan Aykroyd) (1980) and then directed An American Werewolf in London in (1981). He also helped direct Twilight Zone: The Movie (1983).

Landis has also directed the Michael Jackson music videos "Thriller" and "Black or White".

During the filming of Twilight Zone, actor Vic Morrow was decapitated and two child extras, My-ca Dinh Le and Renee Shin-Ye Chen, were killed by a helicopter. The parents of the children sued. At trial, prosecutors attempted to show that Landis was reckless and that he had violated laws relating to child actors by not telling their parents and others about the children's proximity to explosives and helicopters and the hours they could work. He was also accused of negligence in his directions to the crew regarding the use of the helicopter. Landis was acquitted. Vic Morrow’s daughters, Carrie Morrow and actress Jennifer Jason Leigh, also sued and settled out of court for an undisclosed amount.

Other credits include Spies Like Us (1985), ¡Three Amigos! (1986), Coming to America (1988), Beverly Hills Cop III (1994), and The Stupids (1996). He has also directed for television and taken small acting roles in a variety of films, most recently Spider-Man 2 (2004).

Because Landis's list of credits in the late 70s and 1980s include so many beloved classics and crowd pleasers, many peers and film buffs consider him a comedy giant. However, the 1990s saw a string of box office and critical failures, from which Landis's career has yet to recover. Beverly Hills Cop III, directed by Landis in 1994, scored a mere 9 points of 100 possible at the Rotten Tomatoes website. Once an A-list director, Landis's post-80s projects are few, far between, and largely overlooked.

One of Landis' trademarks is to insert references to a fictional film called See You Next Wednesday in movies he directs. The line is from Stanley Kubrick's 2001 as the final goodbye from Frank Poole's parents on the video from them he is watching. Also, for the films he directed for Universal Pictures (Animal House, The Blues Brothers, An American Werewolf in London), there is the famous "Ask for Babs" promo (referring to the character, Babs, in AH) for Universal Studios Hollywood, shown at the end of the credits; of course, contrary to popular belief, there was no such promo and it was just an in-joke by Landis.

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