After graduating, she decided to stay in Chicago, befriending comedians like Megan Stalter, and had a monthly show called Helltrap Nightmare along with Luke Taylor, David Brown, Wyatt Fair, and Scott Egleston.

[21] Sherman was asked to audition for the long-running NBC sketch-comedy show Saturday Night Live after doing a stand-up set at the Just for Laughs festival.

She had previously been asked to perform some showcases for SNL producers and attempted some character-based work which, according to her, "fucking sucked.

[14] At SNL, Sherman frequently collaborates with writer/film producer Dan Bulla, who joined in 2019 for Season 45,[11][25] and with whom she shares an office.

"[25][14] The latter, starring host Josh Brolin, earned a Primetime Emmy Award for Outstanding Production Design for a Variety or Reality Series.

"[28] About a black-and-white pre-taped video suggestive of The Hunchback of Notre Dame, Sherman told Style Weekly, "I was so lucky to have immediately linked up with amazing writers who totally got it.

"[29] Asked about her favorite experience with any performer, Sherman refers to her twisted, gory Scooby-Doo sketch in Season 49: "This past finale, Jake Gyllenhaal was the co-host.

The Late Nighter website added them up in an article, "Sarah Sherman's 'Severed Head' Makes Third SNL Appearance."

[30] Her segments on Weekend Update are popular among the cast and viewers, as she torments Colin Jost, who is willing to be the butt of the joke.

"[29] Her first foray, "Sarah Sherman Roasts Colin Jost," was listed by Mashable at #6 in their ten favorite sketches of 2021, concluding, "She nails it.

"[15][35] Sherman has been praised by critics for adapting her unusual and surreal comedy style to SNL without losing its impact.

Luka Katic of Collider wrote, "Sherman certainly isn't the first unconventional comedian to be featured on SNL (i.e. Tim Robinson, Kyle Mooney, etc.).

Where actors like Robinson often felt they had to tone down their material for SNL, Sherman finds inventive alternative ways to channel her deranged sensibilities into the show.

"[37] Style Weekly wrote, "With her loud clown wear and freakish, squirrel-next-door-vibe, Sarah Sherman is hands down the funniest, most unpredictable cast member.

"[29] WatchMojo describes the "Top 10 Grossest but Hilarious Sarah Squirm Skits on SNL": Bug Assembly; Nickelodeon Show; Spring Flowers; Chucky; Glamgina; Roller Coaster Accident; A Christmas Carol; Eyes; Mail-in Testing Service; and Meatballs.

Sherman enjoys wearing weird outfits, raiding the show's 50 years' worth of costumes and devising new ones.

[11] She once asked Louie Zakarian, the show's multiple-Emmy-Award-winning special-effects makeup chief, to devise a fake seagull that could be impaled in her torso while moving its legs.

Bulla says Sherman talks about visual effects and color palettes: "It's that granular for her, and all of her ideas start like that.

[43] She co-starred in the Adam Sandler comedy film You Are So Not Invited to My Bat Mitzvah (2023)[44] and was cast as a character in downloadable content for the video game High on Life (2022).

[47] Among the artists she has played on the program are Macula Dog, Doug Lussenhop, Johnny Pemberton, Clownvis Presley, Negativland, and The Residents.

[48] On September 5, 2024, Sherman began her guest starring role as dialect coach Robin Finch—for Lois Cerillo, played by Rena Sofer—in the daytime soap opera General Hospital.

"[23] When she started performing stand-up comedy, she took influences from comedians such as Todd Barry, Maria Bamford, and Kristen Schaal.

[40][52] When an interviewer asked why so many of her SNL sketches feature eyeballs, she credited her grandmother: "It's an exposed organ on your head, and it's not that deep.