Despite sharing the Shia faith, Fatimid Egypt and Buyid Iran had unfriendly relations due to conflicting interests over Syria and Jazira.

In the 15th century, Mamluk Egypt and Iran under the Aq Qoyunlu Padishah continued to clash in Upper Mesopotamia, culminating in the Battle of Urfa after a similar Iranian advance into Egyptian dependencies in the decade before.

In the same year, Princess Fawzia of Egypt, the sister of King Farouk I, married Mohammad Reza Pahlavi, the then crown prince (later shah) of Iran.

[13] Contentious issues include Egypt's signing of the Camp David Accords with Israel in 1979, its support for Iraq in Iran's eight-year conflict, the Islamic Republic's hailing of Khalid Islambouli, the President Anwar Sadat's assassin as a religious hero, seeing as there was both a street and mural named after him (however, the honouree was changed to Muhammad al-Durrah, the 12-year-old Palestinian boy shot and killed during the outset of the Second Intifada), and close Egyptian relations with the United States, and most of the Western European countries.

While overall relations have been steadily improving, continued tensions between Iran, Saudi Arabia and allied Western nations have put this development into question.

[12] In July 2013, after the uprising and subsequent overthrow that removed Mohamed Morsi and his Muslim Brotherhood-dominated government, the interim Minister of Foreign Affairs, Nabil Fahmy announced that Egypt seeks stable and positive ties with the Islamic Republic of Iran.

In 2023, in the aftermath of the Chinese brokered Saudi-Iran Deal, Egypt and Iran have had numerous rounds of talks in Oman aimed at restoring relations between the two countries.

In May 2023, Iran's Supreme Leader Ayatollah Ali Khamenei said in a meeting with Oman's Sultan that Tehran welcomes better diplomatic relations with Cairo.