Assisi was the birthplace of St. Francis, who founded the Franciscan religious order in the town in 1208, and St. Clare, the founder of the Poor Sisters, which later became the Order of Poor Clare’s after her death. The 19th-century Saint Gabriel of Our Lady of Sorrows was also born in Assisi.

Around 1000 BC a wave of immigrants settled in the upper Tiber valley as far as the Adriatic Sea, and also in the neighbourhood of Assisi. These were the Umbrians, living in small fortified settlements on high ground. From 450 BC these settlements were gradually taken over by the Etruscans. The Romans took control of central Italy after the Battle of Sentinum in 295 BC. They built the flourishing municipium Asisium on a series of terraces on Monte Subasio. Roman remains can still be found in Assisi: city walls, the forum (now Piazza del Comune), a theatre, an amphitheatre and the Temple of Minerva (now transformed into the Church of Santa Maria sopra Minerva). In 1997, the remains of a Roman villa were also discovered containing several well-preserved rooms with frescoes and mosaics in a condition rarely found outside sites such as Pompei.

In 238 AD Assisi was converted to Christianity by bishop Rufino, who was martyred at Costano. According to tradition, his remains rest in the Cathedral Church of San Rufino in Assisi.

The Ostrogoths of king Totila destroyed most of the town in 545. Assisi then came under the rule of the Lombards as part of the Lombard and then Frankish Duchy of Spoleto.

The thriving commune became an independent Ghibelline commune in the 11th century. Constantly struggling with the Guelph Perugia, it was during one of those battles, the battle at Ponte San Giovanni, that Francesco di Bernardone, (Saint Francis of Assisi), was taken prisoner, setting in motion the events that eventually led him to live as a beggar, renounce the world and establish the Order of Friars Minor.

The city, which had remained within the confines of the Roman walls, began to expand outside these walls in the 13th century. In this period the city was under papal jurisdiction. The Rocca Maggiore, the imperial fortress on top of the hill above the city, which had been plundered by the people in 1189, was rebuilt in 1367 on orders of the papal legate, cardinal Gil de Albornoz.

In the beginning Assisi fell under the rule of Perugia and later under several despots, such as the soldier of fortune Biordo Michelotti, Gian Galeazzo Visconti and his successor Francesco I Sforza, dukes of Milan, Jacopo Piccinino and Federico II da Montefeltro, lord of Urbino. The city went into a deep decline through the plague of the Black Death in 1348.

The city came again under papal jurisdiction under the rule of Pope Pius II (1458–1464).

In 1569 construction was started of the Basilica of Santa Maria degli Angeli. During the Renaissance and in later centuries, the city continued to develop peacefully, as the 17th-century palazzi of the Bernabei and Giacobetti attest.

Now the site of many a pilgrimage, Assisi is linked in legend with its native son, St. Francis. The gentle saint founded the Franciscan order and shares honours with St. Catherine of Siena as the patron saint of Italy. He is remembered by many, even non-Christians, as a lover of nature (his preaching to an audience of birds is one of the legends of his life).

Assisi was hit by two devastating earthquakes that shook Umbria in September 1997. But the recovery and restoration have been remarkable, although much remains to be done. Massive damage was caused to many historical sites, but the major attraction, the Basilica di San Francesco, reopened less than 2 years later.