The 49-year-old tactician, who was sacked by Roma in March, signed a contract with the Genovese club until June 30, 2020.
"Di Francesco is the best choice as our aim is to keep improving Samp," club president Massimo Ferrero said. "He comes with knowledge, experience, good football, desire, and mentality. Welcome, Eusebio!"
Sampdoria finished ninth and a considerable 13 points adrift of Serie A's top six last season. Marco Giampaolo, their handler for the past three seasons, was hired as AC Milan boss on an initial two-year contract Wednesday.
Di Francesco will inherit new summer arrivals Julian Chabot and Morten Thorsby at the Stadio Luigi Ferraris and will be joined by a nine-man backroom team featuring assistant coach Danilo Pierini.