His success brought him prominence as a sex symbol and boosted requests for his acting skills, leading to his role in Texas (2005), directed by Fausto Paravidino and soon to him joining the cast of Romanzo Criminale, playing a monosyllabic, enigmatic thug character in a powerful portrait of a mafiosi community directed by Michele Placido.

[2] In 2006 he acted in The Black Arrow, a TV series broadcast by Canale 5, adapted from the novel by Robert Louis Stevenson, and took on four new film roles: My Brother Is an Only Child (2007), directed by Daniele Luchetti, based on the novel Il fasciocomunista by Antonio Pennacchi.

The Cézanne Affair (2009), directed by Sergio Rubini, co-starred Scamarcio's then partner, Italian-Greek actress, Valeria Golino, who played his sister.

[3] He starred in John Wick: Chapter 2, playing the Italian Mob boss, Santino D'Antonio, the antagonist in the film.

In 2024 he starred as the lead character in the Netflix film Vanished into the Night, directed by Renato De Maria and co-starring Annabelle Wallis.