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. In 1996, Facinelli played opposite his then-future wife Jennie Garth in An Unfinished Affair. Other TV roles followed, including a part in After Jimmy (1996) and a college dropout in Calm at Sunset. Facinelli co-starred with Amanda Peet and Michael Vartan in the 1997 AIDS-themed drama Touch Me (1997) and co-starred as a high school student in two 1998 features with Ethan Embry and Breckin Meyer, Dancer, Texas Pop. 81, and Can’t Hardly Wait, which starred Jennifer Love Hewitt.

Facinelli met actress Jennie Garth on the set of An Unfinished Affair in 1995. Facinelli and Garth married on January 20, 2001, in a traditional Roman Catholic ceremony. They have three daughters. In March 2012, Facinelli filed for a divorce from Garth, which was finalized in June 2013.

Facinelli appeared in the sci-fi film Supernova starring James Spader in 2000. 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. Facinelli had a recurring role in the HBO series Six Feet Under in 2004 and a role in the FX original series Damages beginning in 2007. Facinelli starred in Hollow Man 2 with Christian Slater. It was released direct-to-video in May 2006.

In 2006, he was cast in Touch the Top of the World, a true story of Eric Weihenmayer, the first blind person to climb Mount Everest. The film is based on his best selling autobiography.

In 2009, Facinelli had his Italian citizenship recognized in order to shoot a film in Europe, which required that all actors be European citizens. This was possible because his parents are Italian.

He is the founder of the production company Facinelli Films. Their first feature film, Loosies, which was written entirely by Facinelli, was filmed in 2011. He starred in the film, which is a story of a New York pickpocket that being produced by Verdi Corrente Productions. In 2011 he also wrote and produced the Hallmark Channel telefilm Accidentally in Love which starred his then-wife Jennie Garth. In 2015, he played Maxwell Lord in Supergirl.

Facinelli began dating actress Jaimie Alexander in 2012 after meeting on the set of Loosies. After a break, Facinelli and Alexander became engaged in March 2015. In February 2016, Facinelli and Alexander announced they had called off their engagement. In 2020, he proposed to girlfriend Lily Anne Harrison, the daughter of actors Gregory Harrison and Randi Oakes, in Mexico.

In 2015 Facinelli co-wrote the novel After the Red Rain with Barry Lyga and Robert DeFranco. It is set on a future Earth whose population is grappling with dwindling resources.