It runs west 30 kilometres (19 mi) from the city of Rome to its important sea port of Ostia Antica, from which it took its name.

In the Late Roman Empire, trade suffered under an economic crisis, and Ostia declined as an important port.

With the accompanying growth of importance of the Via Portuensis from the time of Constantine onwards, that of the Via Ostiensis correspondingly decreased.

There are the remains of at least one Roman bridge along the road, which is the Ponte presso Tor di Valle.

On its way to Ostia, the road passes by the important basilica of Saint Paul Outside the Walls.