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McCarthy began appearing on television and in film in the late 1990s. She first gained recognition for her role as Sookie St. James on the television series Gilmore Girls (2000–2007). She played Dena on the ABC sitcom Samantha Who? (2007–2009) before starring as Molly Flynn on the CBS sitcom Mike & Molly (2010–2016), for which she received the Primetime Emmy Award for Outstanding Lead Actress in a Comedy Series in 2011. McCarthy's appearances as a host on Saturday Night Live (2011–2017) led to a win for the Primetime Emmy Award for Outstanding Guest Actress in a Comedy Series in 2017.

McCarthy gained critical acclaim for her performance in the comedy film Bridesmaids (2011), receiving a nomination for the Academy Award for Best Supporting Actress. She went on to star in several commercially successful comedies, including Identity Thief (2013), The Heat(2013), Tammy (2014), St. Vincent (2014), Spy (2015), and The Boss (2016). In 2018, McCarthy received critical acclaim for portraying writer Lee Israel in the biographical film Can You Ever Forgive Me? (2018), earning a nomination for the Academy Award for Best Actress. She has since starred in the drama miniseries Nine Perfect Strangers (2021) and played Ursula in the musical fantasy film The Little Mermaid (2023).

McCarthy and her husband, Ben Falcone, are the founders of the production company On the Day Productions, under which they have collaborated on several comedy films, including Life of the Party (2018), Super Intelligence (2020), and Thunder Force (2021). In 2015, she launched her clothing line for plus-sized women named Melissa McCarthy Seven7. She received a motion picture star on the Hollywood Walk of Fame.