It leaves Rome, goes up the Val Tevere ("Valley of the Tiber") and into the mountains at Castello delle Formiche, ascends to Gualdo Tadino, continuing over the divide at Scheggia Pass, 575 m (1,886 ft) to Cagli.

It remains a country road, while the traffic crosses by railway and autostrada through dozens of tunnels between Florence and Bologna, a shorter, more direct route under the ridges and nearly inaccessible passes.

[2] During the period of Roman expansion in the 3rd and 2nd centuries BC, the Flaminia became, with the sea route, a main axis of transportation by which wheat from the Po valley supplied Rome and central Italy.

Constantine the Great's famous Battle of the Milvian Bridge also occurred on the road, after his nearby dream of the Chi Rho (which led to his conversion and that of the Roman Empire to Christianity).

[3] After the fall of the western Roman Empire the route remained in use, and when the Ostrogothic king Theodahad set out from Ravenna for Rome around 535, a letter of Cassiodorus mentions work done to repair the road.

[4] After the emperor Justinian invaded Italy, competition between the Goths and Romans over strongpoints on the road resulted in more activity through a route that ran slightly to the north through Perugia, the old Etruscan Via Amerina.

In its place was established the 'Byzantine corridor', a new route linking Rome and Ravenna that departed both cities on the Via Flaminia but which was forced due to political circumstances to pass through Perugia rather than Spoleto.

[8] From there it made its way to Ocriculum (Otricoli) and Narnia (Narni), where it crossed the Nera River by the Ponte d'Augusto, the largest Roman bridge ever built, a splendid four-arched structure to which Martial alludes,[9] one arch of which is still standing.

Later, a more circuitous route from Narnia to Forum Flaminii was adopted, increasing the distance by 12 Roman miles (18 km) and passing by Interamna Nahars (Terni), Spoletium (Spoleto) and Fulginium (Foligno) from which a branch diverged to Perusia (Perugia).

[2] From Forum Flaminii, where the two branches rejoined, the Flaminia went on to Nuceria Camellaria (Nocera Umbra) whence a branch road ran to Septempeda and thence either to Ancona or to Tolentinum (Tolentino) and Urbs Salvia (Urbisaglia) and Helvillum (site uncertain, probably Sigillo, but possibly Fossato di Vico), to cross the main ridge of the Apennines, a temple of Jupiter Apenninus standing at or near the summit of the pass according to one ancient author.