The original name of the gate was Porta Ostiensis, as it was located at the beginning of via Ostiense, the road that connected Rome and Ostia.

The gatehouse is flanked by two cylindrical towers, and has two entrances, which had been covered by a second, single-opening gate, built in front of the first by the Byzantine general Belisarius (530s–540s).

Later, it was renamed to the Italian Porta San Paolo, because it was the exit of Rome that led to the Basilica of St. Paul Outside the Walls.

In 549, Rome was under siege; the Ostrogoths of Totila entered through this gate, because of the treason of the Isaurian garrison.

On 10 September 1943, two days after the armistice between the Allies and Italy had been agreed, Italian military and civil forces tried to block German seizure of the city, with 570 casualties.