Culkin was ranked No. 2 in Vh5 and E!'s respective lists, the "100 Greatest Kid-Stars" and "50 Greatest Child Stars".

Culkin was born in Manhattan, New York City, and raised in Yorkville. He is the son of Patricia Brentrup and Kit Culkin, a former stage actor known for his productions on Broadway. Culkin was raised Roman Catholic; he attended a Catholic school (St. Joseph's School of Yorkville) for 5 years before moving on to Professional Children's School. Culkin also studied ballet at the School of American Ballet. Culkin was the third of seven children, five boys and two girls: Shane (born 1976), Dakota (1978–2008), Kieran (born 1982), Quinn (born 1984), Christian (born 1987), and Rory (born 1989). Culkin is the nephew of actress Bonnie Bedelia, his father's sister. During Culkin's early childhood, the family lived in a small apartment; his mother was a telephone operator and his father worked as a sacristan at a local Catholic church.

Culkin began acting at the age of four. Early roles saw him appearing in a stage production of Bach Babies at the New York Philharmonic. He continued appearing in roles on stage, television, and in films throughout the 1980s. Notable parts in this period included an episode of the popular action series "The Equalizer" in which he played the victim of a kidnapping, and also in the TV movie "The Midnight Hour." In 1989 he starred in "Uncle Buck" with John Candy.

Culkin rose to international fame with his lead role as Kevin McCallister in the blockbuster film "Home Alone" (1990), where he was reunited with "Uncle Buck" writer and director John Hughes and "Uncle Buck" co-star John Candy. He reprised the role of Kevin in the 1992 sequel "Home Alone 2: Lost in New York."

Culkin also starred in a Saturday morning cartoon entitled "Wish Kid," and hosted "Saturday Night Live" in late 1991.

By then, Culkin was in high demand and was paid a reported $750,000 by the World Wrestling Federation to serve as the ring bearer in Macho Man Randy Savage's wedding to Miss Elizabeth at SummerSlam in 1991.

Despite the huge success of "Uncle Buck," "Home Alone," "Home Alone 2: Lost in New York," and "My Girl," other films Culkin acted in, such as "The Good Son," only did reasonably well (although he was nominated for MTV Movie Award in the category for Best Villain for his performance in the film). "Getting Even with Dad," "Richie Rich," and "The Pagemaster," all released in 1994, were only mildly successful at the box office. He also appeared in a filmed version of "The Nutcracker" as the title role in 1993, which was staged from the 1954 George Balanchine New York City Ballet version of the ballet. He appeared in the 1998 music video for the song "Sunday" by the rock band Sonic Youth.

After several years of inactivity, Culkin returned to acting in 2000 with a role in the play Madame Melville, which was staged in London's West End. 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-bound, 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.

Culkin began doing voice-over work, with his appearances on Seth Green's "Robot Chicken." In 2006, he published an experimental, semi-autobiographical novel, Junior, which featured details into 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. 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 citing the phrase "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.

In April 2011, Culkin featured in musician Adam Green's experimental film The Wrong Ferarri which was entirely shot on iPhone. In the same month he also appeared in the music video for Stamp Your Name On It performed by Green's former bandmate Jack Dishel/Only Son.

Culkin stated in an May 27, 2004 interview on "Larry King Live," he tends to refrain from disclosing aspects of his personal life, though he discussed his life as a child actor, the conflict in his family life (including his estrangement from his father), and how he retired from child acting at 14. Culkin married actress Rachel Miner in 1998, but the couple later separated in 2000 and divorced in 2002. Culkin began dating actress Mila Kunis in May 2002.

The couple postponed a possible engagement in 2006 with Culkin residing in New York, and Kunis residing in Los Angeles. On January 3, 2011, Kunis' publicist confirmed reports that Culkin and Kunis had ended their relationship several months previously, saying "The split was amicable, and they remain close friends".

On September 17, 2004, Culkin was arrested in Oklahoma City for the possession of 17.3g of marijuana and two controlled substances, 16.5 mg of Alprazolam and 32 mg of Clonazepam, for which Culkin was briefly jailed but soon released on a $4,000 bond. After being arraigned in court for misdemeanor drug offenses, he pleaded not guilty at the trial (October 15, 2004 to June 9, 2005), then later reversed the plea to guilty. His lawyers reached a plea bargain with the state of Oklahoma and Culkin received three one-year suspended prison terms, forced enrollment into a probationary drug treatment program and a $540 fine.

Around the time of the first "Home Alone" movie, Culkin became close friends with pop singer Michael Jackson, making an appearance in Jackson's "Black or White" music video.