After mutineers from Egypt assassinated Uthman, Amr distanced himself from their cause, despite previously instigating opposition against Uthman. In the ensuing First Muslim Civil War, Amr joined Mu'awiya ibn Abi Sufyan, against Caliph Ali () due to promises of the governorship of Egypt and its taxes. Amr served as Mu'awiya's representative in the abortive arbitration talks to end the war. Afterward, he wrested control of Egypt from Ali's loyalists, killing its governor Muhammad ibn Abi Bakr, and assumed the governorship instead. Mu'awiya kept him in his post after establishing the Umayyad Caliphate in 661 and Amr ruled the province until his death.