Symmachus was born on Sardinia (then under Vandal rule), the son of Fortunatus; Jeffrey Richards notes that he was born a pagan, and "perhaps the rankest outsider" of all the Ostrogothic Popes, most of whom were members of aristocratic families.

Symmachus had been baptized in Rome, where he became archdeacon of the Church under Pope Anastasius II.

Pope Anastasius II dies on November 16, 498, after a two-year reign in which he has tried to conciliate followers of Acacius, the late patriarch of Constantinople, who had been excommunicated by Felix III.

He is succeeded on November 22 by Symmachus as the fifty-first pope, in the official papal selection in the Lateran Palace (Rome).

Meanwhile, Antipope Laurentius is elected "pope" in the Basilica di Santa Maria Maggiore on the same day by a dissenting minority faction with Eastern Empire sympathies, who are supported by Emperor Anastasius; this causes a schism over who has been legitimately elected pope by the citizens of Rome.

Both factions agree to allow King Theodoric to arbitrate.

He rules that the one who was elected first and whose supporters are the most numerous should be recognized as pope.

An investigation finds the facts favor Symmachus and his election is recognized as proper.

However, an early document known as the "Laurentian Fragment" claims that Symmachus obtained the decision by paying bribes, while deacon Magnus Felix Ennodius of Milan will later write that four hundred solidi were distributed among influential personages, whom it would be indiscreet to name.