"Panisperna" most probably refers to the tradition of the Poor Clares of the adjacent convent distributing bread and ham, "panis et perna" in Latin[1] on 10 August, the Feast of St. Lawrence.

Tradition states that the first edifice on the site was constructed during the reign of Emperor Constantine I, about 100 years after the martyrdom of St. Lawrence.

The first written evidence of an ecclesiastical edifice on the site is from 1300, when Pope Boniface VIII rebuilt the church and annexed an abbey to it.

The present church is the result of a rebuilding by Carlo Rainaldi in 1575-6 under Pope Gregory XIII.

It was restored and decorated with images of St. Lawrence and St. Francis of Assisi in 1893-4 by Pope Leo XIII.

Pope Leo XIII also constructed a steep flight of steps in front of the church that led to a tree-lined courtyard.

A late 16th-century fresco of the Matryrdom of St. Lawrence serves as the reredos of the high altar and was painted by Pasquale Cati, a pupil of Michelangelo.