Helena was born around 250 in Drepanum in Bithynia (later renamed Helenopolis in her honor). Her social origins were modest — Ambrose calls her a stabularia, possibly 'innkeeper' — and she became the consort (possibly wife, possibly concubine — sources are ambiguous) of Constantius Chlorus, by whom she bore Constantine around 272.

When Constantius was elevated to Caesar in 293, he was required to set Helena aside in favor of a more politically advantageous match. Helena apparently lived in obscurity until her son gained power. After Constantine's victory at the Milvian Bridge (312) and his support for Christianity, Helena was elevated to the rank of Augusta — empress — and became a prominent figure at court.

She converted to Christianity (timing unclear) and was known for piety and charitable work. Around 326-328, in her late seventies, she undertook a pilgrimage to the Holy Land. Eusebius of Caesarea, writing within a few years, records that she founded the Church of the Nativity in Bethlehem and the Church of the Eleona (Ascension) on the Mount of Olives, and distributed alms generously to the poor, freed prisoners, and recalled exiles.

Helena died around 330 in her son's presence. Her body was brought to Rome, where her sarcophagus — an enormous red porphyry monument — survives in the Vatican Museums.

Traditionally, Helena discovered the True Cross during her Jerusalem pilgrimage. According to accounts that developed from the late fourth century onward (first clearly in Ambrose and Rufinus), Helena directed excavations at Calvary and uncovered three crosses. The True Cross was identified when a sick woman (or, in some versions, a corpse) was healed upon touching it. However, Eusebius, who is nearest to the events, does not mention the Cross discovery at all — a significant silence.