Louis Szekely was born in Washington, D.C., the son of Mary and Luis Szekely, an economist. His mother is of Irish Catholic descent and his father, a native of Mexico, is of Mexican Catholic and Hungarian Jewish ancestry. After spending seven years in Mexico City, Szekely's family moved to Massachusetts—first Framingham and then Newton. His family pronounces their surname, Hungarian-origin Szekely, roughly as [se'-kei], and in his grade-school years he resorted to "C.K." as an easy way to get his name pronounced almost correctly as [si' key].

He was married to New York artist and painter Alix Bailey in 1995; they divorced in 2009. He has two daughters from the marriage and shares joint custody of them with Bailey.

His credits as a writer include Late Show with David Letterman, Late Night with Conan O'Brien, The Dana Carvey Show and the Chris Rock Show. His work for the Chris Rock Show was nominated for an Emmy Award three times, including winning "Best Writing in a Variety or Comedy Series" in 1999. He was also nominated for an Emmy Award for his work writing Late Night with Conan O'Brien. However, the feature film born from the Chris Rock sketches, Pootie Tang, received largely negative reviews.[citation needed] He was nominated for an Emmy Award for writing on his 2008 special, Chewed Up.

C.K. has co-written two screenplays with Chris Rock, Down to Earth in 2001, and I Think I Love My Wife in 2007.

He has also directed and written feature-length movies and is perhaps best known for his work on Pootie Tang. In addition to Pootie Tang, he has written and directed one other feature-length film titled Tomorrow Night (which premiered at Sundance in 2000) and several other, shorter films including films for a sketch comedy show on the Showtime cable network.

He has performed his stand-up frequently on shows like Late Show with David Letterman, Late Night with Conan O'Brien, Lopez Tonight, The Tonight Show with Jay Leno, and Jimmy Kimmel Live. In August 2005, C.K. starred in a half-hour HBO special as part of the stand-up series One Night Stand.

In 2006, C.K. starred in his own hour-long HBO special titled Shameless. On March 1, 2008, Louis recorded a stand up special Chewed Up that premiered on Showtime October 4, 2008 and went on to be nominated for an Emmy for "Outstanding Writing in a Comedy or Variety Special." On April 18, 2009, Louis recorded a stand up special entitled Hilarious that will be released as a film in the near future. Hilarious has been accepted by the Sundance Film Festival and will be released sometime in January. It is the first stand-up comedy film to be accepted into Sundance.

In a 2010 interview, C.K. described returning to stand-up and doing specials after his divorce as a year and a half working "to catch up to" the breakup of his marriage which, although portrayed in the HBO series Lucky Louie as fractious, had nonetheless been central to the show and his life. One element of preparation for stand-up was training in the boxing gym, including with locally well-known Lowell, Massachusetts fighter Micky Ward, trying to "learn how to ... do the grunt work and the boring, constant training so that you'll be fit enough to take the beating."

In June 2006, he began starring in Lucky Louie, a sitcom he created. The series premiered on HBO and was videotaped in front of a live studio audience; it was HBO's first series in that format. Lucky Louie is described as a bluntly realistic portrayal of family life. However, HBO canceled the series after its first season. He also plays a small role as a security guard in Role Models. In 2009, he was added to NBC’s Parks and Recreation, where he appeared in a multi-episode story arc as a potential love interest for Amy Poehler’s character.

In August 2009, FX picked up his new series Louie. In it C.K. is starring, writing, directing, and editing. The show features his stand-up routines blended with skits of things that have happened in his life. The show premiered on June 29, 2010. The show has been picked up for thirteen episodes. It addresses life as divorced father, aging (42), liberal: "It's hard to start again after a marriage," he started in one of his early routines on the show. "It's hard to really, like, look at somebody and go, hey, maybe something nice will happen. ... Or you'll meet the perfect person, who you love infinitely, and you even argue well, and you grow together, and you have children, and then you get old together, and then she's going to die."