According to tradition, the inhabitants had asked for protection from the heavens during the 5th-century AD invasions of the Vandals; on the feast of Saint Apollinare, a dense fog came down and the invaders spared the town.

In 771–772, refugees came here from Tiro, a small centre placed on the hill of Civita (later "Svignata"), when the original Etruscan town of Grotte di Castro was destroyed by the Lombards under king Desiderius.

Due to its location along the Via Cassia, in a central position for the interests of Orvieto, Viterbo and Sovana, San Lorenzo alle Grotte had been always of strategic importance and was contended for by local noblemen and the Church.

On 20 March 1298, Boniface VIII ordered to stop all hostilities and let Orvieto's army occupy the castle of San Lorenzo.

In 1315, San Lorenzo was involved in the fights between Orvieto and the papal legate Bernard of Cluny, being defeated at Montefiascone by Guittuccio of Bisenzio.

In 1354, in the presence of Gil Alvarez De Albornoz, all villages of Val di Lago confirmed their submission to Orvieto.

An agreement was achieved between San Lorenzo and Grotte di Castro about rights and duties of land owners residing in their respective territories.

Cardinal Giovanni Angelo Braschi, future Pope Pius VI, at the time when he was apostolic treasurer, after the many failures in trying to decontaminate the area, induced Pope Clement XIV to take the decision to move all homes from the hollow, unhealthy areas by the lake to a higher and more liveable place, in order to be safe from the frequent floods which hit the plains.

An area was identified on a wide upland in the vicinity of the old village (in a location named Gabelletta) and next brought on mandate of the Reverend Apostolic Chamber.

As a sign of gratitude, two years later the citizens created and put on view a marble frame in memory of the saviour and founder of the new town.

On 22–23 February 1798 on his way to Florence as prisoner of the French, Pius VI had the opportunity to stop by San Lorenzo Nuovo for an address to the population.

In May–June 1944, in the course of World War II, San Lorenzo Nuovo suffered aerial bombardment by Allied forces, with numerous casualties and substantial damages.

In April–May 2006, to celebrate 500 years in the line of duty a group of veteran Swiss Guards marched from Switzerland, stopping in San Lorenzo Nuovo on their way to Rome.

Road Cassia, over the tract between Acquapendente and Bolsena, at km 124, crosses through an octagonal square, just in front of the parish church of San Lorenzo Martire.

This is the centre of San Lorenzo Nuovo, Piazza Europa, a wide square regarded as an interesting example of 18th century urban planning.

The artist Francesco Navone adopted an innovative technique meant to create the plan of the new town in the style of Copenhagen Amalienborg square.

Little differences can be noticed between the nobles' and the common people's houses, the only exception being San Lorenzo Martire, which stands out of the other buildings for its considerable height.

The only entrance door is flanked by two small windows, from which, even when the church is closed, visitors can take a look inside for a prayer or to leave a flower on the windowsill.

Inside, the hall is plastered in white, the arches of the side chapels are in excellent handmade red tuff and the presbytery is decorated with floral motifs and architectural elements in faux marble.

From the polychrome stained-glass window of the oculus of the apse, where the monogram of Mary's name surmounted by a royal crown stands out, a warm and dazzling light enters on sunny days.

The church houses an Umbrian-Latin school fresco of the Virgin Mary on the throne, with the sweetest face and the blessing Christ Child naked on his mother's knees and a carnation to the right, dating back to the 15th century (likely 1475).

The octagonal church, dedicated to Saint John the Baptist, was rebuilt in 1563 by the architect Pietro Tartarino, an apprentice of Alberto da Sangallo.

The area included woodlands such as Selva del Lamone and Monti di Castro, with isolated caves and small rivers out of the main roads.

One of the latest brigands of northern Latium, in action at the end of the 19th century when the area became part of the Kingdom of Italy, was Fortunato Ansuini.

A trail is marked in the area across Onano, Grotte di Castro, Gradoli and San Lorenzo Nuovo where the adventures of Ansuini and other brigands set their stage.

The town's main square is transformed into a large, open-air restaurant where the visitors can taste potato gnocchi, and other typical local recipes such as pigskin beans, tripe, and roasted sausages.

A special atmosphere is created by liscio and rock orchestras in the context of cultural, sporting and religious (patron saint day and Assumption of Mary) events.

Originated from the long lasting tradition of football match Pergolino-Convento (since 2000 memorial "Antonio Cimpella"), it consists of an array of sporting competitions combined with popular games.

It was a biblical exodus of herds of oxen and horses coming from the Maremma, wagons loaded with all kinds of merchandise, chickens tied for the legs of poor beasts in bunches like onions, rabbits in cages, chicks of all species of poultry, passed the endless flocks of sheep, pigs in packs and isolated.

According to an ancient popular tradition, the wooden crucifix dating back to the 12th century and housed in the parochial church is object of deep veneration.