After winning the Battle of Ajnadayn, the Muslim armies marched north and laid siege to Damascus. To isolate the city from the rest of the region Khalid placed detachments south on the road to Palestine and in the north at the Damascus-Emesa route, and several other smaller detachments on routes towards Damascus. Heraclius' reinforcements were intercepted and routed at the Battle of Sanita-al-Uqab, 30 kilometres (20 mi) from Damascus. Khalid's forces withstood three Roman sallies that tried to break the siege.

The city was taken after a monophysite bishop informed Khalid ibn al-Walid, the Muslim commander in chief, that it was possible to breach city walls by attacking a position only lightly defended at night. While Khalid entered the city by assault from the Eastern gate, Thomas, commander of the Byzantine garrison, negotiated a peaceful surrender at the Jabiyah gate with Abu Ubaidah, Khalid's second in command. After the surrender of the city, the commanders disputed the terms of the peace agreement. Damascus was the first major city of the Eastern Roman Empire to fall in the Muslim conquest of Syria.