Born Mohamed Gaber Mohamed Abdallah in El-Sayeda Zeinab, the popular Cairo quarter, El-Sherif changed his career path from playing football for Zamalek Club to studying at the Higher Institute of Theatrical Arts.

His fellow actor Adel Emam introduced him to the late director Hassan Al-Emam, and in 1967 he debuted in the film Kasr El-Shawk (The Palace of Desire), marking the launch of his illustrous career.

El-Sherif, one of Egypt's most prominent actors for half a century, had an impressive oeuvre of around 175 films and more than 30 TV series and tens of plays and radio dramas.

His significant works include a lead role in the 1982 film Hadduta Misriya (An Egyptian Story), as well as the 1991 film Nagui Al-Ali, in which he portrayed the iconic Palestinian cartoonist.

El-Sherif also produced a number of works in which he acted. All his self-produced films were successful both critically and commercially. These include, among others, The Circle of Vengeance (1976), Shams' Stroke (1978), Cat on a Hot Tin Roof (1977), Always My Lover (1980), The Last of the Respectable Men (1984), The Times of Hatem Zahran (1987), Nagy Al-Ali (1992) as well as The Lovers (2001), which was El-Sherif's directoral debut.

El-Sherif believed in the importance of supporting young directors, especially Higher Institute of Cinema graduates. This encouraged them to present their projects to him before any other actor. Thus, Nour was a common denominator in the debuts of Samir Seif, Mohamed Khan, Atef Al-Tayeb, and Mohamed El-Naggar, to name a few.

In the 2000s, at the peak of his career, El-Sherif continued to collaborate with many renowned directors including Marwan Hamed in The Yacoubian Building (2006), Sandra Nashaat in Transit Prisoner (2008), Adel Adib in The Night of the Baby Doll (2008) and Amir Ramses in Cairo Time (2015).

Cairo Time was his last film after which he began to suffer from a continuous health crisis until he died 11 August 2015.

In 2021 Google celebrated 75th birthday of El-Sherif writing in the doodle's caption: "El-Sherif was renowned for the attention to detail he poured into his craft and his devotion garnered awards from prestigious institutions across Arab entertainment. The Alexandria International Film Festival, which El-Sherif had collaborated with since its inception, honoured him with its Lifetime Achievement Award in 2014."

The same year (2014), El-Sherif was honored during 11th edition of Dubai International Film Festival.

In 2016, one year following El-Sherif's passing, the 9th edition of National Theatre Festival was named after him.

In 2023, celebrating the actor's birthday, his daughter May wrote a letter published by Al Ahram Arabic gate. It opened with the words: "I miss you a lot. I wish I could sit with you, hug you and tell you a lot of things; and take your advice."

May goes on to thank her father for his presence in life, art and among people. "You made Sarah's and my life so exceptional," May added referring to her sister.