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 her portrayal of writer Lee Israel in the biographical film Can You Ever Forgive Me?

She has since starred in the drama miniseries Nine Perfect Strangers (2021) and played Ursula in the musical fantasy film The Little Mermaid (2023).

In 2015, she launched her own clothing line for plus-sized women, named Melissa McCarthy Seven7, and she received a motion picture star on the Hollywood Walk of Fame.

[16] McCarthy is an alumna of The Groundlings, an improvisational and sketch comedy troupe based in Los Angeles, California.

[17] She also performed in New York City as a drag queen under the moniker Miss Y, including at the Wigstock festival.

In 2007, she starred opposite Ryan Reynolds in the science fantasy psychological thriller The Nines, written and directed by John August.

[27] Television critic Lucy Mangan from the Guardian commended McCarthy and her co-star Billy Gardell on some “unfeasibly delicate and charming work”, while decrying the show itself for hanging every one of its gags on the subject of their weight.

[28] In 2011, McCarthy had a breakout performance in the comedy film Bridesmaids alongside Kristen Wiig, Maya Rudolph, Rose Byrne, Wendi McLendon-Covey and Ellie Kemper.

[33][34] In fall 2011, after achieving fame from Bridesmaids, she received her first Primetime Emmy Award for Outstanding Lead Actress in a Comedy Series for her role on Mike & Molly.

[39] She was nominated five times for a Primetime Emmy Award for Outstanding Guest Actress in a Comedy Series for her appearances on the television show from 2011 to 2017, winning in 2017.

McCarthy owns 'Identity Thief' with a turn of limitless surprise, making an otherwise adequate comedy soar as a star vehicle.

She is riveting in simply-penned moments of remorse and confession, adding tearful depth to her ace timing and formidable physical comedy.

[56] On Rotten Tomatoes, the site's critical consensus reads, "Melissa McCarthy remains an engaging screen presence, but her efforts aren't enough to keep the jumbled Tammy on track.

"[57] Later in 2014, McCarthy played the female lead, opposite Bill Murray, in the comedy-drama film St. Vincent, directed and written by Theodore Melfi.

[67] Tom Russo of The Boston Globe credited the film's success to McCarthy, writing, "part of what makes the action comedy such a loopy blast is the identity shifts she pulls on the audience.

"[68] Bill Goodykoontz of Arizona Republic called the film McCarthy's return to form, writing "Finally, after the promise shown in Bridesmaids, but sold short since by weak scripts in films like Tammy and Identity Thief, Melissa McCarthy gets a movie vehicle worthy of her talents.

On February 4 and 11, 2017 she made surprise appearances on Saturday Night Live portraying White House Press Secretary Sean Spicer.

McCarthy played a wannabe environmentalist, who has a series of mishaps befall her such as being capsized by a whale, being charged by a rhino, and falling down a crevasse.

She also starred in The Happytime Murders, an adult puppet buddy cop crime comedy film directed by Brian Henson.

[87] She executive produced and starred in the Hulu limited thriller drama series, Nine Perfect Strangers.

The Guardian's Lucy Mangan said: "Most engagingly, there is Melissa McCarthy, sweeping all before her as charismatic, bestselling author Frances, who has recently been dealt harsh blows and is here to have pampered time to recover.

As is so often the case with the magnificent McCarthy, she is the best, most arresting thing in the series, and every time she comes back on screen you wriggle with delight.

On June 28, 2019, it was announced that McCarthy was in talks to play Ursula in Disney's film The Little Mermaid, set to be directed by Rob Marshall.

Dolled up to look like Divine’s evil-stepsister in her glowing green lair, the comic star’s just delicious as the movie’s deep-sea villain.

Her timing is impeccable, and though the part is virtually identical to the one Pat Carroll originated, she aces what’s demanded of these tricky remakes: Basically, McCarthy manages to hit every beat the super fans expect, while surprising with every pause and inflection.

Vivian and Georgette both made an appearance in the 2016 film The Boss, with the former playing a younger version of her mother's character.

Falcone often makes cameo appearances in McCarthy's films and TV series, such as a third-season episode of Gilmore Girls, The Nines, Bridesmaids, The Heat, Tammy, Identity Thief, Spy, The Boss, Life of the Party, The Happytime Murders, Thunder Force, Can You Ever Forgive Me?