Sennott gained critical attention for her breakout role in Shiva Baby (2020), which earned her a Gotham Award nomination for Breakthrough Actor.

[11] In 2018, feeling out of control of her fledgling career, Sennott turned to Twitter comedy; she wrote and tweeted multiple short jokes per day.

[13] In 2019, she was named one of the six best comedians of the alt scene on lists from both Time Out New York and Pop Dust, which cited her unique satirical takes on aspects of millennial life and culture.

[23][24] Sennott also appears with Edebiri and other comedians on the web comedy-documentary series Speak Up, which seeks to amplify female voices about working in comedy.

[a] Megan Conway of The New York Times Style Magazine summarized the consensus surrounding her performance: "Sennott's ability to inject an astonishing range of meaning into Alice's various cries and yowls—as well as her litany of expletives and 'oh my Gods'—steals the show.

"[43] In 2023, Sennott reunited with Shiva Baby writer-director Emma Seligman to write the teen sex comedy film Bottoms.

Writing on Sennott's performance in her review for The Austin Chronicle, Jenny Nulf said it "is heartbreaking, a tight rope walk between funny and sad that's done gracefully.

[46] It premiered at the 76th Cannes Film Festival where it was met with highly unfavorable critical reception, though Alex Barasch of The New Yorker commended Sennott as one of its "strong performances.

[49] On March 18, 2024, Deadline reported that Sennott had sold a half-hour comedy pilot to HBO, in which she is set to write, star, and executive produce.