Francesco Caputo's early strike counted for little as Di Francesco set up goals for Kevin-Prince Boateng and Gianmarco Ferrari before finding the net himself after Empoli's Miha Zajc was shown a second yellow card for diving with 19 minutes left.
It was an impressive display from Di Francesco, who was the player spat at by Juventus' Douglas Costa last week which led to the Italian rejecting reports he had racially abused Costa in the moments leading up to the offence.
The game started well for Empoli, with Stefano Sensi being caught in possession before Leonardo Capezzi squared for Caputo to score.
But 12 minutes later Sassuolo were level, with Di Francesco teeing up Boateng to slot home a third goal in four games.
Di Francesco flicked on Domenico Berardi's 57th-minute corner for Ferrari to head the hosts into the lead and the winger finished the scoring with five minutes left courtesy of a clever back-heel flick