Mogontiacum was a place of outstanding importance in Roman antiquity. The city originated as a legionary camp, or castrum, strategically located on a hill opposite the mouth of the Main River. Two legions were stationed here under the command of Drusus, the stepson of Emperor Augustus, to conquer northern Germania. Another camp was built near Weisenau, probably close to a Celtic settlement named after the god Mogon. He was the patron saint of the camp and later of the city.

Mogontiacum quickly developed into the military and then also the civilian center of the region. Emperors repeatedly used Mainz as their headquarters during military campaigns. In the wake of the approximately 12,000 soldiers, settlements of craftsmen and merchants were established near both camps. Gradually, various ports sprang up on the banks of the Rhine. The inhabitants erected all the buildings typical of a Roman city: temples, forums, simple dwellings and city villas for the wealthy citizens, monuments to the gods and thermal baths. Outside the settlements, avenues of tombs developed. A permanent bridge connected Mainz and the small outpost of Kastel on the right bank of the Rhine as early as 27 AD. In the first century, a theater with 10,000 seats was also built.

After the unrest of the Year of the Four Emperors in 69/70, the camp was rebuilt in stone. A Roman aqueduct was constructed, carrying fresh water from Finthen to the legionary camp over a distance of 9 kilometers. Before the year 90, Mainz became the capital of the new province of Upper Germania.

The city flourished for over two centuries until, in the 3rd century, Germanic raids made the borders of the empire, the Limes, increasingly insecure. Around 250, a stone city wall was erected, which in later years enclosed an increasingly smaller area. In 368, the Alemannic prince Rando devastated the city, and in 406, the tribes of the Vandals, Suebi, and Alans did so a second time. Their attack hit the city hard and marked the beginning of the decline of Roman Mainz.