The fact that it was situated astride the Via Egnatia ensured that Amphipolis was an important urban centre in Early Christian times. Saint Paul passed through the city in AD 49/50, on his way from Philippi to Thessaloniki, and taught the message of Christianity.
After the new religion had established itself, Amphipolis became an episcopal see (by AD 692) and developed into an important religious center, as is clear from the four, luxurious (marble revetment, wall mosaics, floor mosaics, and opus sectile). Early Christian basilicas (5th-6th c.), and the bishop's residence, and above all from the majestic hexagonal 6th century church, one of the few Early Christian centralised churches in Greece.
In the 8th-9th c., after the city appears to have suffered raids by the Slavs, a section of the population founded the fortified city of Chrysoupolis on the site of ancient Eion at the mouth of the river Strymon. Archaising Byzantine writers continued to refer to Amphipolis by its old name, though the city was now called Popolia.
The area retained its strategic importance (on the route to the interior) and was a metochion of the monasteries on Mount Athos, as is evident from the erection of two defence and storage towers either side of the Strymon. (One of these was built in 1367 by the founders of the Pantokratoros Monastery on Mount Athos).