Amr Youssef 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 garnered him widespread 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 also received much praise for his role in the TV series Grand Otel (Grand Hotel) (2016), which won him the Best Actor award at the Murex D’Or in Lebanon. Grand Otel is the first Egyptian series to be available on Netflix.

He then starred in the TV series Asham Iblis (Devil's Wish) in 2017, 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, the NRJ Egypt Cup Award for Best Actor, and an honor at the 2018 Nile Drama Awards.

In 2019, Youssef starred in Welad Rizk 2 (Sons of Rizk 2), which made more than EGP 100m in the Egyptian box-office and won him the DG Excellence Award at the DearGuest Festival. Then, in 2020, he landed a starring role in the series Nemra 2, which premiered on Shahid VIP.

Amr's latest works in 2022 include the TV series Waad Iblis (The Devil's Promise), which was directed by the British Colin Teague and is now available on Shahid VIP.

Youssef also featured in the 2023 Ramadan marathon, in which he starred in the epic military TV series El Kateeba 101 (BATTALION 101), which was written by Eyad Saleh and directed by Mohamed Salama.

Furthermore, he is set to appear in Karim El-Sobky’s romantic movie She'o opposite Dina El-Sherbiny and Mohamed Mamdouh.

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