The monastery of St Francis, belonging to the Franciscan Order of the Minori Osservanti, was established before 1242 on the site now occupied by the Archaeological Museum of Heraklion, along the eastern side of the old fortifications, which it incorporated as its enclosure. The monastery was particularly wealthy, receiving numerous donations, possessing important sacred relics, and maintaining a rich library. Among the works that adorned the church were paintings attributed to Titian and Giovanni Bellini.

The large monastic church, built in the form of a free cross and distinguished by its polygonal apse, was visible from the harbour. Converted into a mosque during the Ottoman period, it fell into ruin after the earthquake of 1856, with the exception of a single chapel. Building material from its demolition was reused in the construction of the Vezir Mosque (St Titus) and other structures in the city. Architectural members from its elaborate portal — donated to the monastery by Pope Alexander V (Peter Philargos, formerly a monk at the Franciscan monastery of St Anthony at Kares, Mirabello) — were incorporated into the entrance of the Ottoman barracks of St George (now the Law Courts).

Between 1904 and 1907, the first Archaeological Museum of the city was erected over the ruins of the church. In 1937, during the construction of the second, larger museum building, the surviving chapel was also demolished. More recently, excavation works for the expansion of the Museum brought to light the lower part of the apse and the southern arm of the transept, which had been formed as an underground funerary crypt. Near the foundations of the apse, a large lead seal of Pope Gregory XI (1370–1378), bearing representations of the Apostles Peter and Paul, was uncovered, indicating that the original church was reconstructed in the 14th century.