Amurri Martino had a role in the 2002 film The Banger Sisters, in which her mother starred, with Amurri Martino playing the daughter of her mother's character. She guest-starred, along with her mother, on an episode of Friends in Season 7 Episode 15 ("The One with Joey's New Brain") in which she is slapped by Sarandon. In 2004, she appeared in Saved!. She guest-hosted Attack of the Show with Kevin Pereira. She had a role in the third season of the Showtime series Californication, where she played Jackie, a stripper, student and love interest of central character Hank Moody. Amurri Martino played the leading role in the 2008 film Middle of Nowhere.

In 2009, she appeared as Shelly in the episode "The Playbook" of How I Met Your Mother. Amurri Martino starred in the thriller film Isolation, directed by Stephen T. Kay.

In 2010, she appeared in the Fox series House as Nicole in the episode "The Choice". In 2012, she appeared in Happy Madison Production's That's My Boy as young Mary McGarricle. Her mother also appeared in the film as McGarricle's older self.

Amurri married former Major League Soccer player and current NBC Sports broadcaster Kyle Martino on October 29, 2011. They have two children, a daughter, Marlowe Mae, (born August 2014) and a son, Major James, (born October 2016). In August 2015, Amurri Martino revealed they had a miscarriage at nine weeks. Amurri Martino is a longtime resident of Pound Ridge, New York.