In the late 13th century, Cardinal Giacamo Colonna renovated the monastery and ceded it to the Poor Clares. Some scholars argue that San Lorenzo was intended to be a family church like San Silvestro in Capite, a location where Colonna family wealth could be displayed while looking pious rather than greedy. Others argue, however, that this interpretation minimizes some of the unique circumstances of the convent’s founding

Giancomo handpicked all of the nuns for the convent and gave them a degree of freedom from the papacy with carefully timed gifts of land. That, coupled with Giancomo’s links to so-called “deviant” Franciscan groups who were slightly outside the religious norm, indicates that rather than a family church, San Lorenzo in Panisperna may have been a sort of haven for female Franciscans who may have experienced conflict with religious authority. His sister, the Colonna Saint Margherita who had died several years prior, is an example of one of these women. One of the convent’s most notable residents, Saint Bridget of Sweden, had much in common with Margherita and came to Rome after she experienced a divine vision instructing her to do so. Further strengthening this interpretation is the conflict that Giancomo experienced with Pope Boniface the VIII, indicating a potential wariness towards the papacy and a desire to create spaces outside of its direct control.

The church retained significance within the urban space due to its proximity to Santa Maria Maggiore and the city center. In fact, during the sack of Rome in 1527, the Clares at San Cosimato in Trastevere crossed the Tiber to take shelter in the more centrally located church.