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The comedy Mrs. Doubtfire (1993), starring Robin Williams, was another box-office success for Columbus. He went on to direct several other films throughout the 1990s, which were mostly met with lukewarm reception. However, he found commercial success again by directing the film adaptations of J. K. Rowling's novels Harry Potter and the Sorcerer's Stone (2001) and its sequel, Harry Potter and the Chamber of Secrets (2002). In addition to directing, Columbus was a producer for Harry Potter and the Prisoner of Azkaban (2004), as well as the drama The Help(2011). He also directed the fantasy Percy Jackson & the Olympians: The Lightning Thief(2010) and the 3D action comedy Pixels (2015).

Columbus is the co-founder of 1492 Pictures, a film production company that has produced some of his films since 1995. More recently, he co-founded another production firm with his daughter in 2014 called Maiden Voyage Pictures. In 2017, he launched ZAG Animation Studios, alongside Michael Barnathan, Haim Saban, and Jeremy Zag. Columbus is also known for his collaboration with composer John Williams, with whom he had worked on the film Home Alone and the film series Harry Potter.