Columbus graduated from Tisch School of the Arts. He created and wrote the first episodes of the animated series Galaxy High (1986–87).
Columbus made his directorial debut with the teen comedy Adventures in Babysitting (1987). He had huge success with the popular Home Alone film (1990) and its sequel Home Alone 2: Lost in New York starring Macaulay Culkin.
In 1995, Columbus started his own production company named 1492 Pictures. This refers to Columbus's more famous namesake, christopher Columbus.
His later directorial work includes Mrs. Doubtfire (1993), Stepmom (1998), Bicentennial Man (1999), the first two Harry Potter films and Rent (2005), an adaptation of the popular Broadway Musical.
Commercially, he has been hugely successful, despite the occasional flop, but like his one-time mentor, Stephen Spielberg, he has met with critical accusations of excessive sentimentality and catering to children, as well as being described as a "bean counter" by British film critic Mark Kermode in criticism to his "bland and straight-forward direction."
As of August 2006, Columbus optioned the film rights to Christopher Moore's best-selling novel A Dirty Job.