Aiming to make a name for himself in the film and TV industry, Amr Youssef started his career as a TV commercials model in 2002, and then worked as a TV presenter in Rotana Cinema in 2005. He made his acting debut in 2007 when producer Mohamed Fawzy introduced him to Egyptian veteran actor Nour El Sherif and he eventually played the role of the journalist, Adham Fares, in season one of El Daly TV series. After playing several TV roles, Youssef landed his first film role in Maklab Haramiya (Thieves Prank) (2009), followed by Nour Einy (The Light of My Eyes) (2010).

His successful TV roles include the role of Karim George in the TV hit El Mowaten X (Citizen X) (2009), which gained him wide audience acclaim. In the same year, Amr starred in the film Wahid Saheeh (The Right One), and in 2013, he starred in the TV hit Niran Sadeeqa (Friendly Fire). Two years later, he played one of his most important film roles as Rabea’ in the box-office hit Welad Rizk (Sons of Rizk). In 2016, Youssef starred in three blockbusters: Hepta: The Last Lecture, Kedbet Kol Youm (Everyday Lie), and Al-Thaman (The Price).

Youssef gained wide acclaim for his role in Grand Otel (Grand Hotel) (2016) TV series, which won him the Best Actor award at the Murex D’Or in Lebanon. Grand Otel is the first egyptian series to show on Netflix. That was followed by another successful performance in the 2018 TV series Tayea', which won him many awards, including the Best Arab Actor in a TV role at the Egyptian Catholic Center Cinema Festival, the DG Excellence Award at the DearGuest Festival, and an honor at the 2018 Nile Drama Awards for his role in Tayea'. In 2019, Youssef starred in Welad Rizk 2 (Sons of Rizk 2) that made more than EGP 100 million in the box-office and won him the DG Excellence Award at the DearGuest Festival. His latest drama Nemra 2 has been officially released in 2020.

Besides acting, Amr graced the cover of several international magazines like GQ Middle East.