Born at Prato round about the year 1335, he was the son of Marco di Datino, a merchant registered with the guild of tavern-keepers who was resident in Porta Fuia, and of Monna Vermiglia. Both parents died of the plague in 1348, together with two others of their children, Nofri and Vanna.
Francesco and Stefano, the two surviving brothers, were taken under the guardianship of Piero di Giunta del Rosso, a relative of theirs, and they were welcomed into the house of Monna Piera di Pratese Boschetti who acted as mother to them.
After working in various workshops in Florence where he learnt the skills of accounting and commerce, in 1350 Francesco moved to Avignon which was a flourishing commercial centre and the seat of the pope. His brother joined him in 1353. Very few traces of that period of activity remain in his archives.

In 1354, Piero di Giunta purchased for him "uno chasolare, i' sullo chanto dello Porcellaticho", the first nucleus of what was to become the Datini's Palace.
In Aprile 1359, Francesco returned to Prato for a few months to settle up with his guardian, who in actual fact waived his right to a fee for this service. Her property amounted to 207 florins.

On 15 July that same year he returned to Avignon, where, in 1376, married Margherita, young daughter of Domenico, son of Donato Bandini, who were a Florentine merchant in French. In remaining Avignon's ledgers we can find the expenses for this sumptuous marriage. Her marital relationship with Margherita, whose we have a significant documentation in her correspondence's editions, caused many discussions by scholars.

Until 1363 (when the first documents of the DATINI's ARCHIVE date from), the young Francesco continued his learning of the trade of commerce in his job as office boy in a local firm. He became a working partner in the company of Niccolò di Bernardo on 13 July of that year. A historical record and three books of Pledges testify to this company which was dissolved in 1367.