He appears to have been an African by birth, but of his personal history nothing is known. He was elected after a period of sede vacante lasting from the death of Pope Eusebius on 17 August 310 or, according to others, 309, soon after Eusebius was exiled to Sicily.
Miltiades became pope after the Roman emperor Galerius had passed an edict of toleration ending the persecution of Christians. During his pontificate, in 313, the Edict of Milan was passed by the tetrarchs Constantine and Licinius, declaring that they would be neutral with regard to religious worship and restoring church property. Constantine presented the pope with the Lateran Palace which became the papal residence and seat of Christian governance.
In the same year 313, Miltiades presided over the Lateran Synod in Rome at which Caecilian was acquitted of the charges brought against him, and Donatus Magnus was condemned as a heretic (see Donatism). He was then summoned to the Council of Arles, the first representative meeting of the Western Roman Empire's Christian bishops, but died before it was held.
The Liber Pontificalis, compiled from the fifth century onwards, attributed the introduction of several later customs to Miltiades.
In the thirteenth century, the feast of Saint Melchiades (as he was then called) was included, with the mistaken qualification of "martyr", in the Roman Calendar for celebration on 10 December. In 1969 it was removed from that calendar of obligatory liturgical celebrations, and his feast was moved to the day of his death, 10 January, with his name given in the form "Miltiades" and without the indication "martyr".