The basilica was founded by the Roman Emperor Constantine I over the burial place of Paul of Tarsus, where it was said that, after the apostle's execution, his followers erected a memorial, called a cella memoriae. This first basilica was consecrated by Pope Sylvester in 324.[1]

In 386, Emperor Theodosius I began erecting a much larger and more beautiful basilica with a nave and four aisles with a transept. It was probably consecrated around 402 by Pope Innocent I. The work, including the mosaics, was not completed until Leo I's pontificate (440–461). In the 5th century, it was larger than the Old Saint Peter's Basilica. The Christian poet Prudentius, who saw it at the time of emperor Honorius (395–423), describes the splendours of the monument in a few expressive lines.

Under Leo I, extensive repair work was carried out following the collapse of the roof on account of fire or lightning. In particular, the transept (i.e. the area around Paul's tomb) was elevated and a new main altar and presbytery were installed. This was probably the first time that an altar was placed over the tomb of Saint Paul, which remained untouched, but largely underground given Leo's newly elevated floor levels. Leo was also responsible for fixing the triumphal arch and for restoring a fountain in the courtyard (atrium).

Under Pope Gregory the Great (590–604), the main altar and presbytery were extensively modified. The pavement in the transept was raised and a new altar was placed above the earlier altar erected by Leo I. The position was directly over Saint Paul's sarcophagus.

In that period, there were two monasteries near the basilica: Saint Aristus's for men and Saint Stefano's for women. Masses were celebrated by a special body of clerics instituted by Pope Simplicius. Over time, the monasteries and the basilica's clergy declined; Pope Gregory II restored the former and entrusted the monks with the basilica's care.

The basilica was damaged in an earthquake on 29 April 801. Its roof collapsed, but was rebuilt by Leo III.

As it lay outside the Aurelian Walls, the basilica was damaged in the 9th century during a Saracen raid. Consequently, Pope John VIII (872–882) fortified the basilica, the monastery, and the dwellings of the peasantry,[2] forming the town of Johannispolis (Italian: Giovannipoli) which existed until 1348, when an earthquake totally destroyed it.

In 937, when Odo of Cluny came to Rome, Alberic II of Spoleto, Patrician of Rome, entrusted the monastery and basilica to his congregation and Odo placed Balduino of Monte Cassino in charge. Pope Gregory VII was abbot of the monastery and in his time Pantaleone, a rich merchant of Amalfi who lived in Constantinople, presented the bronze doors of the basilica maior, which were executed by Constantinopolitan artists; the doors are inscribed with Pantaleone's prayer that the "doors of life" may be opened to him.[3] Pope Martin V entrusted it to the monks of the Congregation of Monte Cassino. It was then made an abbey nullius. The abbot's jurisdiction extended over the districts of Civitella San Paolo, Leprignano, and Nazzano, all of which formed parishes.

 Cloister of the monastery of San Paolo fuori le mura

The graceful cloister of the monastery was erected between 1220 and 1241.

From 1215 until 1964, it was the seat of the Latin Patriarch of Alexandria.

Pope Benedict XIV undertook the restoration of the apse mosaic and the frescoes of the central nave, and commissioned the painter Salvatore Manosilio to continue the series of papal portraits, which at that time ended with Pope Vitalian, who had reigned over a millennium earlier.[4]

On 15 July 1823, a workman repairing the copper gutters of the roof started a fire that led to the near-total destruction of this basilica, which, alone among all the churches of Rome, had preserved much of its original character for 1435 years.[1] More recent studies indicate that the cause of the fire could be different from that indicated by official sources.[5] Marble salvaged from the burnt-out Saint Paul's was re-laid for the floor of Santo Stefano del Cacco.[6]

In 1825, Leo XII issued the encyclical Ad plurimas encouraging donations for the reconstruction. A few months later, he issued orders that the basilica be rebuilt exactly as it had been when new in the fourth century, though he also stipulated that precious elements from later periods, such as the medieval mosaics and tabernacle, also be repaired and retained. These guidelines proved unrealistic for a variety of reasons and soon ceased to be enforced. The result is a reconstructed basilica that bears only a general resemblance to the original and is by no means identical to it. The reconstruction was initially entrusted to the architect Pasquale Belli, who was succeeded upon his death in 1833 by Luigi Poletti,[7] who supervised the project until his death in 1869 and was responsible for the lion's share of the work. Poletti also asked the scientist Angelo Secchi to design an automatic fire detection and extinguishing system, which was later removed.[8] Many elements which had survived the fire were reused in the reconstruction.[1] Many foreign rulers also made contributions. Muhammad Ali Pasha, Viceroy of Egypt gave columns of alabaster, while the Emperor of Russia donated precious malachite and lapis lazuli that was used on some of the altar fronts. The transept and high altar were consecrated by Pope Gregory XVI in October 1840,[9] and that part of the basilica was then re-opened. The entire building was reconsecrated in 1854 in the presence of Pope Pius IX and fifty cardinals. Many features of the building were still to be executed at that date, however, and work ultimately extended into the twentieth century. The quadriporticus looking toward the Tiber was completed by the Italian Government, which declared the church a national monument. On 23 April 1891, an explosion at the gunpowder magazine at Forte Portuense destroyed the basilica's stained glass windows.

On 31 May 2005, Pope Benedict XVI ordered the basilica to come under the control of an archpriest and he named Archbishop Andrea Cordero Lanza di Montezemolo as its first archpriest.