She began acting in local theater productions as a teenager and performed improv and sketch comedy at the Upright Citizens Brigade Theatre.

After graduating from New York University Tisch School of the Arts, Plaza made her feature film debut in Mystery Team (2009) and gained wide recognition for her role as April Ludgate on the NBC political satire sitcom Parks and Recreation (2009–2015).

From 2017 to 2019, Plaza portrayed the Shadow King and Lenny Busker in the critically praised FX superhero series Legion, and produced and starred in the 2017 black comedy films The Little Hours and Ingrid Goes West.

She also starred in the romantic comedy Happiest Season and thriller Black Bear (both 2020) as well as produced and played the title character in the crime film Emily the Criminal (2022).

[25][26] As a teen, Plaza's aunt gave her a job at a video store, during which she discovered her love of independent films and filmmakers that inspired her, such as John Waters and Christopher Guest.

She then played a standup comic and Seth Rogen's love interest in the black comedy-drama film Funny People, directed by Judd Apatow.

[33] As she did not have experience performing standup, she signed up for open mic nights at comedy clubs and bars in New York City to prepare for the role.

[41][16] When Plaza flew to Los Angeles for Funny People, the film's casting director Allison Jones asked her if she wanted to attend other meetings while she was in the city.

At the meeting, they told her the idea for the show's pilot and that they were considering giving Amy Poehler's character an assistant who was a doltish blonde.

[42][13][6][41] Plaza, who said that in real life she was like Poehler's earnestly hard-working character, took inspiration from her younger sister for April's apathetic disposition.

[2][45] While Plaza was in Los Angeles for Funny People and Parks and Recreation, Allison Jones also recommended that she audition for Edgar Wright's romantic action comedy film Scott Pilgrim vs. the World (2010).

[33][16] On March 12, 2010, Plaza performed at A Night of 140 Tweets: A Celebrity Tweetathon for Haiti, produced by Rob Huebel, Paul Scheer, Ben Stiller, and Mike Rosenstein, at the Upright Citizens Brigade Theatre in Los Angeles.

[49][50] In 2012, Plaza had her first starring role in a major film in the comedy Safety Not Guaranteed, playing a magazine intern who answers a curious want ad.

[33] In 2016, Plaza starred in Mike and Dave Need Wedding Dates alongside Zac Efron, Anna Kendrick, and Adam DeVine.

Then, she was a guest star on HarmonQuest, as a gnome named "Hawaiian Coffee" and portrayed Aaron Burr in the "Hamilton" episode of Drunk History.

[67] In 2020, Plaza played Riley Johnson in the romantic comedy Happiest Season,[68] and produced and starred in the independent experimental thriller Black Bear, garnering critical acclaim for her performance.

[73] In 2021, Plaza wrote and made her directorial debut with the episode "Quiet Illness" of the Showtime anthology series Cinema Toast.

She edited various film and television clips starring Young into a psychological thriller about a woman's self-esteem, and cast Christina Ricci as a voice narrator.

[84] In the second season of the HBO anthology series The White Lotus, Plaza portrayed Harper, a lawyer vacationing in Sicily with her husband.

[93][94] In July, it was announced that she would be making her stage debut in an off-Broadway revival of John Patrick Shanley's Danny and the Deep Blue Sea, a two-hander about strangers who become lovers after meeting at a dive bar, opposite her Black Bear costar Christopher Abbott.

[1] In 2024, Plaza and her Parks and Recreation costar Nick Offerman reunited in a Mountain Dew ad that aired during the Super Bowl LVIII broadcast.

[100] Plaza portrays the future self of Elliott Labrant in the comedy film My Old Ass (2024), and TV presenter Wow Platinum in Francis Ford Coppola's epic science fiction drama Megalopolis (2024).

[114][115][116] According to the review aggregator site Rotten Tomatoes, Plaza's most critically acclaimed films include Scott Pilgrim vs. the World (2010), Safety Not Guaranteed (2012), Ned Rifle (2014), Ingrid Goes West (2017), The Little Hours (2017), Black Bear (2020), Happiest Season (2020), Emily the Criminal (2022), and My Old Ass (2024).

Her most critically acclaimed television projects include Parks and Recreation (2009–2015), Legion (2017–2019), Calls (2021), Little Demon (2022), The White Lotus (2022), Scott Pilgrim Takes Off (2023) and Agatha All Along (2024).