A flight of Emirates Airlines carrying the Prime Minister departed Milan Malpensa International Airport at 1:45pm local time (BdST 6:45pm).
Bangladesh Ambassador to Italy Abdus Sobhan Sikder saw her off at the airport.
The flight is scheduled to reach Hazrat Shahjalal International Airport at 8:10am on Saturday.
On Tuesday last, the Prime Minister arrived in Rome at the invitation of her Italian counterpart Giuseppe Conte.
During her stay, Sheikh Hasina held talks with Italian Prime Minister Conte on Wednesday where both the leaders agreed to take the bilateral relations to a new height increasing trade and business.
Besides, the Prime Minister attended a civic reception accorded in her honour, which was arranged by the Italy chapter of Awami League on Tuesday and inaugurated the Chancery Building of Bangladesh Embassy in Rome on Wednesday.
Sheikh Hasina also had an audience with Pope Francis, the spiritual leader of the Catholics of the world, at the Holy See (Vatican City) on Thursday morning.
The Prime Minister later left Rome by train for Milan on Thursday.