Malesani takes over from Eusebio Di Francesco, who was sacked on Tuesday after 19 months in charge following the team's poor run of form.
A statement from Sassuolo read: "Sassuolo Calcio announces it has appointed Alberto Malesani as the new coach of the first team.
"Mr Malesani will guide this afternoon's training session and will be unveiled to the media on Thursday."
Malesani inherits a team that sits 18th in the standings, one point behind safety after 21 games played.
Sunday's 3-1 defeat at Livorno was Sassuolo's sixth loss in their last seven league games.
The 59-year-old Malesani, who has 21 years' experience of coaching in Italy, had been out of a job since being dismissed by Palermo in February 2013.
His first game in charge will be against one of his former clubs, Hellas Verona, on Sunday.