Had we come to this church when it was first built we would still have been able to hear the sounds of chariots and the crowd inside the nearby Circus Maximus, one of the great symbols of the Roman Empire. Now the stadium, like the empire that built it, is nothing more than ruins and memory, while the Faith it strove to crush by the execution of martyrs like St. Anastasia is still here. Little remains of factual history of her story, other than remembering her martyrdom in Sirmium, in modern day Serbia. Her cult arrived in Rome towards the end of the fifth century from Constantinople.
This was originally a district of Roman houses and shops, part of which was demolished to build a small, Greek cross plan church by Pope St. Damasus in the late fourth century. It is possible that this church was originally sponsored by a member of the Imperial family named Anastasia and named in her honor, later being rededicated in honor of St. Anastasia when devotion to her spread to Rome. Another saint associated with this church is St. Jerome. There is a tradition that when staying in Rome he would often celebrate Mass here, possibly because he came from the same region as St. Anastasia. Around the year 500, the nave was extended, giving the church approximately the same dimensions it has today. The unequal width of the aisles, with the right being slightly wider, is a result of older structures being used as foundations for this addition. As the practice of stational Masses during Lent developed, this was assigned as the collectum for the procession to St. Sabina, and as a result, the processional crosses used for the stational processions were kept here when not in use. Another role of the church during this period was as the chapel to the exarch (governor and representative) in Rome of the Byzantine Emperor, who lived on the Palatine Hill. As a result of this, the pope would come to personally celebrate Mass here on Christmas morning, which was also the feast of St. Anastasia.
Pope Leo III refurbished the church at the turn of the ninth century, and with an ambo being given by Innocent III in 1210. Remains of the original Roman and Gothic windows of the right clerestory can still be seen if one looks back to the church from the area of the Circus Maximus. Sixtus IV undertook a renovation from 1471-1484, which was followed by another in 1510. This presaged a wave of additions and changes over the next two centuries. In 1580, the chapel off of the right aisle was added. Five years later the high altar was constructed, being moved to its present location in 1644. The chapel off the left aisle, balancing that across the nave, was added in 1615, and the current façade was constructed from 1634 to 1640. Finally, the interior underwent a massive renovation in 1721-1722, giving it the appearance it has today. The pillars separating the nave from the aisles were reconfigured, and the walls and ceiling covered with stucco decoration. Minor restorations were carried out in the course of the nineteenth century.