Following her early acting and stand-up roles on television, Slate gained recognition for her live variety shows in New York City and for co-creating the children's short film and book series Marcel the Shell with Shoes On (2010–2014) with Dean Fleischer Camp, whom she was married to from 2012 to 2016.

Slate became more widely known as a cast member on the 35th season of Saturday Night Live in 2009, followed by her roles in the sitcoms Bob's Burgers (2012–present), Parks and Recreation (2013–2015), House of Lies (2013–2015), and Kroll Show (2013–2015).

Slate's breakout role came with her leading performance in Gillian Robespierre's coming-of-age dramedy film Obvious Child (2014), for which she won the Critics' Choice Movie Award for Best Actress in a Comedy.

She also appeared in the Daniels' critically acclaimed film Everything Everywhere All at Once (2022), winning the Screen Actors Guild Award for Outstanding Performance by a Cast in a Motion Picture.

[12] After graduating from Milton Academy as valedictorian,[5] Slate attended Columbia University as a literature major,[7] where she helped form the improv group Fruit Paunch,[13] starred in the Varsity Show[14] and met Gabe Liedman, who would become her comedy partner.

[21] They describe their relationship as a "nonsexual romance"; Slate says, "I like to think of us as kind of like [Seinfeld characters] Elaine Benes and George Costanza, but we like each other.

[35] In 2014, Slate starred in the comedy-drama film Obvious Child, which follows the life of a young stand-up comic as she grapples with an unplanned pregnancy and eventual abortion.

Slate exited the role on June 24, 2020, writing on Instagram that "At the start of the show, I reasoned with myself that it was permissible for me to play Missy because her mom is Jewish and White — as am I.

Her character's original name was changed to Debbie the Dog Mom for the film's digital release due to its association with Jewish stereotypes.

Slate lived in Cobble Hill, Brooklyn, before moving with filmmaker Dean Fleischer Camp to Los Angeles in the early 2010s.

[44] In September 2019, Slate announced her engagement to art curator and author Ben Shattuck, owner of Davolls General Store.