Santa Prassede is one of a number of early Christian churches located on the Esquiline Hill when this, the most densely inhabited part of the city, was still strongly pagan. Noble families, who had been converted to Christianity, used parts of their residences, called "domus ecclesia", for religious celebrations.

It seems that this particular church was built on the house site of one such Patrician. However, this origin cannot be verified because this site has never been excavated. Though, written records do date the church back to the beginning of the 5th century.
In the 9th century, Pope Pascal I, catering to the medieval interest in relics, completely reconstructed the building and then had the remains of 2000 martyrs transferred here from the catacombs. Rome was an important center for pilgrims who, through their spending, helped the Roman economy flourish.
The entrance to the church is a small medieval vestibule which totally belies the extraordinary richness of the interior. Here, the 9th century mosaics decorating the triumphal arch, the apse and the wonderful chapel of San Zenone are among the most important in Rome. The chapel, also called the Garden of Paradise, houses the putative pillar at which Christ was scourged in Jerusalem.