[8] Her father is of English and Scottish descent (the Kirkes being a junior branch of a family of Nottinghamshire landed gentry and descending also from the Gibson-Craig baronets)[9][10] and her mother is Jewish.

[20] In late 2017 to early 2018, she had a show at Sargeant's Daughters, a Lower East Side gallery,[21] where she exhibited portrait-style paintings, some of them neck-up, others full-figure, of women in their wedding dresses.

[24] In September 2022, Kirke presented for Batsheva Hay's spring collection at Ben's Kosher Deli.

[26] Kirke reunited with Dunham in the HBO series Girls, appearing in all six seasons from 2011 to 2017 as the character Jessa Johansson.

In September 2017, Kirke appeared opposite Zayn Malik in his music video for the song "Dusk Till Dawn".

In 2021, Kirke appeared in the Netflix series Sex Education in the role of Hope, headmistress of Moordale Secondary School.

In 2021, it was announced that Kirke had accepted a role in Conversations with Friends, a series based on the book of the same name by Sally Rooney, in which she plays Melissa, an older, experienced writer fascinated by a younger couple.

[32] She would go onto direct other projects including multiple music videos and a satire short film with Alex Cameron.