She is known for playing Tracy McConnell in the CBS sitcom How I Met Your Mother from 2013 to 2014, and Sofia Falcone in the HBO crime drama series The Penguin (2024).

[13] Of her performance, Ben Brantley of the New York Times wrote: "It's not easy playing a winsome life force with a foreign accent.

She brings a new confidence to her portrayal, and an enhanced mixture of wit and wisdom, which suggests a maturity in youth, a fatalism hard won during an Eastern European childhood.

[16] Milioti portrayed Jordan Belfort's first wife, Teresa Petrillo, in the 2013 Martin Scorsese film The Wolf of Wall Street.

[20] In 2021, she starred in the HBO Max dark comedy series Made for Love as the entrapped wife of a tech billionaire from whom she runs away.

[21] In 2024, Milioti starred as Sofia Falcone in the HBO spin-off miniseries of The Batman titled The Penguin, opposite Colin Farrell.

[25][26] In February 2021, Milioti worked with PETA in a video featuring Rupert which advocated for adopting a dog over purchasing one from breeders.