Macaulay Carson Culkin was born in New York City. His father, Christopher Cornelius "Kit" Culkin, is a former actor known for his productions on Broadway and is the brother of actress Bonnie Bedelia. His mother is Patricia Brentrup, who never married Culkin. He was named Macaulay after Thomas Babington Macaulay and Carson after Kit Carson of the Old West.

In the spring of 2003, he made a guest appearance on the NBC sitcom Will & Grace. His role as Karen Walker's deceptively immature divorce lawyer won him favorable reviews. Culkin headed back into motion pictures in 2003 with Party Monster, in which he played a role very different from those he was known for; that of party promoter Michael Alig, a drug user and murderer. He quickly followed that with a supporting part in Saved!, as a cynical wheelchair-using, non-Christian student in a conservative Christian high school. Though Saved! only had modest success at the box office, Culkin received positive reviews for his role in the film and its implications for a career as an adult actor. In 2004, he appeared in the music video for the song "Sunday" by the rock band Sonic Youth. Culkin began doing voice-over work, with appearances in Seth Green's Robot Chicken.  In 2006, he published an experimental, semi-autobiographical novel, Junior, which featured details about Culkin's stardom and his shaky relationship with his father.  Culkin starred in Sex and Breakfast, a dark comedy written and directed by Miles Brandman. Alexis Dziena, Kuno Becker and Eliza Dushku also star in this story of a couple whose therapist recommends they engage in group sex. Shooting for the film, Culkin's first since Saved!, took place in September 2006. The film opened in Los Angeles on November 30, 2007 and was released on DVD on January 22, 2008 by First Look Pictures. Culkin's next project was a role in the thirteen-episode NBC television series Kings as Andrew Cross.  In 2009, Culkin appeared in a UK-based commercial for Aviva Insurance (formerly Norwich Union) to help promote their company's rebranding. Culkin stared into the camera stating, "Remember me." On August 17, 2009, Culkin made a brief cameo appearance on WWE Raw at the Scottrade Center in St. Louis, Missouri, following a "falls count anywhere" match between Hornswoggle and Chavo Guerrero, in which Guerrero was defeated by the classic Home Alone gag of rigging a swinging paint can to hit him upon opening a door. Culkin appeared in the doorway and said, "That's not funny." In February 2010, Culkin appeared in an episode of Poppy de Villeneuve's online series for The New York Times, The Park. On March 7 of the same year, he appeared alongside actors Matthew Broderick, Molly Ringwald, Judd Nelson, Ally Sheedy, Anthony Michael Hall, and Jon Cryer in a tribute to the late John Hughes.

What other voice overs did he do?