According to Christian tradition, the basilica was consecrated circa 325 to house the relics of the Passion of Jesus Christ brought to Rome from the Holy Land by Empress Helena, mother of Roman Emperor Constantine I.

It was on her initiative that the large rectangular hall was transformed into a Christian basilica around 320, originally covered by a flat ceiling, illuminated by twenty windows placed five on each side and with valuable marble decoration in the lower register.

(The Sessorium's larger civil hall, built in the style of a three-aisled columned basilica, is still partially preserved as a free-standing apse ruin.)

[2] After the Basilica fell into neglect, Pope Lucius II restored it in the 12th century, giving it a Romanesque appearance, with a nave, two aisles, belfry, and porch.

In 1062 Pope Alexander II installed the Canons Regular of San Frediano di Lucca, who abandoned it during the period of the Avignonese papacy.

On Good Friday popes themselves walked barefoot, as a sign of penance, along the road that connected Saint John Lateran (official Cathedral of Rome) to the basilica of Santa Croce to come and venerate the relic of the Passion of Jesus.

In the vault is a mosaic designed by Melozzo da Forlì, created some time before 1485 and depicting Jesus Blessing, Histories of the Cross, and various saints.

In 1601, during his first stay in Rome, Peter Paul Rubens was commissioned by Archduke Albert of Austria to paint his first altarpiece, St. Helena with the True Cross, for one of the side chapels.

[5] Several famous relics of disputed authenticity are housed in the Cappella delle Reliquie, built in 1930 by architect Florestano Di Fausto, including part of the Elogium or Titulus Crucis, i.e. the panel which was hung on Christ's Cross (generally either ignored by scholars[6] or considered to be a medieval forgery[7]); two thorns of the Crown of Thorns; part of a nail; the index finger of St. Thomas; and three small wooden pieces of the True Cross.

[8] The apse of the Basilica includes frescoes telling the Legends of the True Cross, attributed to Melozzo, Antoniazzo Romano, and Marco Palmezzano.