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The basilica was founded by the Roman Emperor Constantine I over the burial place of Saint Paul, where it was said that, after the Apostle's execution, his followers erected a memorial, called a cella memoriae. This first edifice was expanded under Valentinian I in the 370s.
In 386, Emperor Theodosius I began erecting a much larger and more beautiful basilica with a nave and four aisles with a transept; 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 St. 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. As it was dedicated also to Saints Taurinus and Herculanus, martyrs of Ostia in the 5th century, it was called the basilica trium Dominorum ("basilica of Three Lords").
Under Gregory the Great (590–604) the basilica was extensively modified. The pavement was raised to place the altar directly over Paul's tomb. A confession permitted access to the Apostle's sepulcher.

In that period there were two monasteries near the basilica: St. Aristus's for men and St. 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 Saint Gregory II restored the former and entrusted the monks with the basilica's care.
As it lay outside the Aurelian Walls, the basilica was damaged in the 9th century during the Saracen invasions. Consequently, Pope John VIII (872–882) fortified the basilica, the monastery, and the dwellings of the peasantry, forming the town of Joannispolis (Italian: Giovannipoli) which existed until 1348, when an earthquake totally destroyed it.
In 937, when Saint 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.[2] 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. But the parish of San Paolo in Rome is under the jurisdiction of the cardinal vicar.
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.
The Holy Doors.
Arnolfo di Cambio's tabernacle
On 15 July 1823 a fire, started through the negligence of a workman who was repairing the lead of the roof, resulted in the almost total destruction of the basilica which, alone of all the churches of Rome, had preserved its primitive character for 1435 years. It was re-opened in 1840, and reconsecrated 1855 with the presence of Pope Pius IX and fifty cardinals. Completing the works of reconstruction took longer, however, and many countries made their contributions. The Viceroy of Egypt sent pillars of alabaster, the Emperor of Russia the precious malachite and lapis lazuli of the tabernacle. The work on the principal facade, looking toward the Tiber, was completed by the Italian Government, which declared the church a national monument. On 23 April 1891 an explosion at Porta Portese destroyed the stained glasses.
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.