Facinelli was a regular on the Showtime comedy-drama series Nurse Jackie, portraying the role of Dr. Fitch "Coop" Cooper.

Facinelli made his feature film debut in Rebecca Miller's Angela in 1995 and came to the attention of critics in the TV-movie The Price of Love later that year.

He made appearances in Riding in Cars with Boys in 2001 and The Scorpion King in 2002, followed by a leading role in the Fox drama Fastlane.

In 2006, he was cast in Touch the Top of the World, a true story of Erik Weihenmayer, the first blind person to climb Mount Everest.

After wrapping up Finding Amanda with Matthew Broderick, Facinelli played Carlisle Cullen in the film adaptation of Twilight, based on the book by Stephenie Meyer.

[9] He played Dr. Fitch Cooper for seven seasons on the Showtime dark comedy series Nurse Jackie.

[11] In 2011 he also wrote and produced the Hallmark Channel telefilm Accidentally in Love which starred his then-wife Jennie Garth.

[15] Facinelli began dating actress Jaimie Alexander in 2012 after meeting on the set of Loosies.

[22] In 2009, Facinelli acquired Italian citizenship through jus sanguinis to shoot a film in Europe that required that all actors be European citizens.