Constans grew increasingly fearful that his younger brother, Theodosius, could oust him from the throne; he therefore obliged Theodosius to take holy orders and later had him killed in 660. However, having attracted the hatred of the citizens of Constantinople, Constans decided to leave the capital and to move to Syracuse in Sicily.

On his way, he stopped in Greece and fought the Slavs at Thessalonica with success. Then, in the winter of 662–663, he made his camp at Athens. From there, in 663, he continued to Italy. He launched an assault against the Lombard Duchy of Benevento, which then encompassed most of Southern Italy. Taking advantage of the fact that Lombard king Grimoald I of Benevento was engaged against Frankish forces from Neustria, Constans disembarked at Taranto and besieged Lucera and Benevento. However, the latter resisted and Constans withdrew to Naples. During the journey from Benevento to Naples, Constans II was defeated by Mitolas, Count of Capua, near Pugna. Constans ordered Saburrus, the commander of his army, to attack the Lombards again, but he was defeated by the Beneventani at Forino, between Avellino and Salerno. In 663 Constans visited Rome for twelve days—the only emperor to set foot in Rome for two centuries—and was received with great honor by Pope Vitalian (657–672).