The Diocletianic or Great Persecution was the last and most severe persecution of Christians in the Roman Empire. In 303, the emperors Diocletian, Maximian, Galerius, and Constantius issued a series of edicts rescinding Christians' legal rights and demanding that they comply with traditional religious practices. Later edicts targeted the clergy and demanded universal sacrifice, ordering all inhabitants to sacrifice to the Roman gods (Jews were exempt). The persecution varied in intensity across the empire—weakest in Gaul and Britain, where only the first edict was applied, and strongest in the Eastern provinces. Persecutory laws were nullified by different emperors (Galerius with the Edict of Serdica in 311) at different times. Traditionally, the reign of Constantine the Great (306–337 AD) and Licinius' Edict of Milan in 313 have marked the end of the persecution.

Christians had been subject to intermittent local discrimination in the empire. Roman Emperors before Diocletian were reluctant to legislate against Christianity. In the 250s, under the reigns of Decius and Valerian, Roman subjects including Christians were compelled to sacrifice to Roman gods or face imprisonment and execution, but there is no evidence that these edicts were specifically intended to attack Christianity. After Gallienus's accession in 260, these laws went into abeyance. Diocletian's assumption of power in 284 did not mark an immediate reversal of imperial inattention to Christianity, but it did herald a gradual shift in official attitudes toward religious minorities. In the first fifteen years of his rule, Diocletian purged the army of Christians, condemned Manicheans to death, and surrounded himself with public opponents of Christianity. Diocletian's preference for activist government, combined with his self-image as a restorer of past Roman glory, foreboded the most pervasive persecution in Roman history. In the winter of 302, Galerius urged Diocletian to begin a general persecution of the Christians. Diocletian was wary and asked the oracle at Didyma for guidance. The oracle's reply was read as an endorsement of Galerius's position, and a general persecution was called on 23 February 303.

Persecutory policies varied in intensity across the empire. Whereas Galerius and Diocletian were avid persecutors, Constantius was unenthusiastic. Later persecutory edicts, including the calls for universal sacrifice, were not applied in his domain. His son, Constantine, on taking the imperial office in 306, restored Christians to full legal equality and returned property that had been confiscated during the persecution. In Italy in 306, the usurper Maxentius ousted Maximian's successor Severus, promising full religious toleration. Galerius ended the persecution in the East in 311, but it was resumed in Egypt, Palestine, and Asia Minor by his successor, Maximinus. Constantine and Licinius, Severus's successor, signed the Edict of Milan in 313, which offered a more comprehensive acceptance of Christianity than Galerius's edict had provided. Licinius ousted Maximinus in 313, bringing an end to persecution in the East.