Di Francesco took over as Lecce boss over the summer, but has failed to transform the side that narrowly avoided relegation from the top flight last season.
A club statement read: “US Lecce announce the collaboration with Eusebio Di Francesco has been resolved today. We wish to express a sincere thanks for the work done until now.
“US Lecce also confirm an agreement has been reached with Serse Cosmi to take control of the first team.”