She is known for playing neurosurgeon Dr. Amelia Shepherd on the ABC medical drama Grey's Anatomy (2010–present) and its spin-offs Private Practice (2010–2013) and Station 19 (2020–2024).

[6][7] In 1998, she had a role in one installment of CBC Radio's The Mystery Project called Peggy Delaney as Amber, an estranged fifteen-year-old daughter who comes from Vancouver to stay with her mom for a school term in Toronto.

Scorsone had her breakthrough after landing the leading role in the Lifetime crime drama series Missing, from 2003 to 2006.

[8] She was cast after Eric Stoltz, who was directing one of the show's episodes, heard about the role of Amelia and remembered Scorsone from working with her on My Horrible Year!

He mentioned her to Shonda Rhimes and commented on the resemblance Scorsone had to Patrick Dempsey (the actor who plays Derek Shepherd).

[9] She appeared in the third episode of the seventh season of Grey's Anatomy where Amelia and Derek started to reconcile their differences.