In 1989, Mullally tested for the co-starring role of Elaine Benes on Seinfeld. Mullally in 1998 landed the role of Karen Walker, Grace Adler's sarcastic, pill-popping assistant, in the NBC sitcom Will & Grace. She won the Primetime Emmy Award for Outstanding Supporting Actress in a Comedy Series in both 2000 and 2006, and was nominated in 2001, 2002, 2003, 2004, and 2005. She won the Screen Actors Guild Award for Outstanding Performance by a Female Actor in a Comedy Series three times, in 2002, 2003 and 2004, and with cast members Eric McCormack, Debra Messing, and Sean Hayes, she shared the Screen Actors Guild Award for Outstanding Performance by an Ensemble in a Comedy Series in 2001. She is the first of only two actresses to win a SAG Award three years in a row. She was nominated each year from 2000 until 2003 for the Golden Globe Award for Best Supporting Actress – Series, Miniseries or Television Film.

In 2005, Mullally saw comedian and actor Bill Hader performing with his Second City class in Los Angeles, and shortly thereafter brought Hader to the attention of Saturday Night Live producer Lorne Michaels. Also in 2005, Mullally was awarded the Women in Film Lucy Award "in recognition of her innovation in creative works that have enhanced the perception of women through the medium of television". Following Will & Grace, Mullally hosted her own talk show, The Megan Mullally Show from 2006 to 2007. She has hosted Saturday Night Live, guest-hosted the Late Show with David Letterman, hosted the 2006 TV Land Awards, and been a featured performer twice on the Tony Awards. She has been featured in advertisements for M&M's, Old Navy, CheapTickets.com, and I Can't Believe It's Not Butter.

Mullally guest-starred as 'Bev', an adoption case worker for Liz Lemon in the season-three premiere of NBC sitcom 30 Rock and returned to play the same character two additional times during the show's run. Other appearances include Kathy Griffin: My Life on The D-List, Campus Ladies, director/actor David Wain's Wainy Days, an episode of HBO's Funny or Die, and the Funny or Die web video "That's What She Said."

Mullally has guest-starred seven times as Tammy Swanson on the NBC series Parks and Recreation, in the episodes "Ron and Tammy," "Ron & Tammy: Part Two," "Li'l Sebastian," "Ron and Tammys," "The Trial of Leslie Knope," "Ron and Diane," and "Ron and Jammy". Mullally plays the role of the second ex-wife of the character Ron Swanson, who is played by her real-life husband, Nick Offerman. Offerman also had a part on one episode of Mullally's show Will & Grace where he played a plumber that came to Will's mother's house while Will, Karen, Grace, and Jack were visiting.

Also in 2009, Mullaly starred in the ABC sitcom In the Motherhood. Based on the original web series, the television adaptation focuses on three mothers. She played Rosemary opposite Cheryl Hines and Jessica St. Clair. The series was poorly received and was canceled by ABC due to low ratings after airing just five out of seven episodes produced. Mullally co-starred in 2010 as Lydia on the Starz ensemble series Party Down. Mullally co-starred as "Chief" on the Adult Swim series Childrens Hospital. In 2011, Mullally began a recurring role as Dana Hartz, the mother of Penny (Casey Wilson), on the ABC sitcom Happy Endings. In the following months, Fox announced Mullally would join the series Breaking In when the show returned for a second season on March 6, 2012.

She will star in the Will & Grace reboot in 2017.

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