On 19 June 2012, Di Francesco was appointed the head coach of Serie B side Sassuolo. At the end of 2012–13 season, he guided Sassuolo to the Serie B championship and promotion to the top-flight campaign. He was sacked on 28 January 2014 after a poor run of results, only to be re-appointed to the post on 3 March 2014 after results did not improve in his absence. From March 2014 onwards, results improved and Di Francesco successfully coached to save Sassuolo from relegation thanks to a run of positive results (13 points in the final seven games of the season). In June 2014, it was announced Di Francesco had signed an extension that will keep him contracted with Sassuolo until June 2016. He extended his contract again in April 2016, which would last until June 2019. Sassuolo finished the 2015–16 Serie A season in sixth place, sealing a spot in the third qualifying round of the 2016–17 UEFA Europa League. The following season, Sassuolo managed to advance to the Europa League play-offs under Di Francesco, and eventually sealed a spot in the Europa League group stage.
