The most immediate threat to the empire under his reign were the Arabs, who sent a fleet to attack Constantinople by sea in 674. While Constantine was diverted by this, the Slavs attacked Thessalonika.

Constantinople survived the Arab siege until 678, when the Byzantines employed Greek fire against the Arab fleet at the Battle of Syllaeum. This was one of the first times Greek fire was used in combat. The Arabs withdrew, and were almost simultaneously defeated on land in Anatolia.

In 680 Constantine called the Sixth Ecumenical Council (also known as the Third Council of Constantinople), reaffirming the doctrines of the Council of Chalcedon in 451. This solved the controversy over monothelitism; conveniently for the empire, most monothelites were now under the control of the Arab caliphate.

He also had his brothers Heraclius and Tiberius mutilated so they would be ineligible to rule. This ensured the succession of Justinian II when Constantine died of dysentery in 685.