Her starring role in the Netflix dark comedy series Dead to Me (2019–2022) earned her a nomination for a Primetime Emmy Award for Outstanding Lead Actress.

Her other credits include Legally Blonde (2001), Brokeback Mountain (2005), Daddy's Home (2015) and its 2017 sequel, The Founder (2016), Green Book (2018), A Simple Favor (2018), and The Curse of La Llorona (2019).

[8] Cardellini graduated from St. Francis High School in Mountain View in 1993[9] and then moved to Los Angeles to seek roles in television and film.

[13] Cardellini received her first big break role in 1996 as Sarah on ABC's Saturday morning live-action children's series, Bone Chillers.

Cardellini starred in the first season of the AMC series The Lot in 1999,[10] and spent the summer in Europe as part of a touring production of Lancelot, a fourteenth-century Dutch tragedy.

Cardellini acted for six seasons on ER until the series finale, "And in the End...", and with the cast won the TV Land ensemble Icon Award in 2009.

In 2007, Cardellini was chosen to play lovelorn Clara in the CBS miniseries Comanche Moon, a prequel to 1989's Lonesome Dove.

Cardellini voice acts periodically on the podcast and live show The Thrilling Adventure Hour, on the Sparks Nevada: Marshal on Mars segments.

For her performance on Mad Men, she received a nomination for the Primetime Emmy Award for Outstanding Guest Actress in a Drama Series.

[28] For her performance, she received critical acclaim and a nomination for the Primetime Emmy Award for Outstanding Lead Actress in a Comedy Series.

That same year, she co-starred with Viggo Mortensen and Mahershala Ali in the film Green Book, which won the Academy Award for Best Picture.