Sassuolo were made to regret missing numerous scoring opportunities, as Empoli turned it around with two late goals from Andrea Pinamonti and Szymon Zurkowski.
Alessio Dionisi took Empoli to promotion by winning the Serie B title last season and switched over to Sassuolo in the summer. He was fresh from a shock 2-1 win away to Juventus in the midweek round and had Jeremie Boga back, although Filip Djuricic joined Pedro Obiang and Filippo Romagna on the treatment table. Federico Di Francesco made his comeback from injury, while Samuele Ricci sat out a ban.
The visitors started strong, Andrea Pinamonti hitting the side-netting and Federico Di Francesco stinging Andrea Consigli’s gloves at the near post.
Pinamonti thumped the frame of the goal on 26 minutes, but the offside flag only went up afterwards.
Guglielmo Vicario rushed off his line for a decisive block on Hamed Junior Traore and the deadlock was broken just before half-time.
Traore burst down the left and his cross took a massive deflection off Lorenzo Tonelli to wrong-foot Vicario at the near post.
Empoli came out fighting for the second half, as Liam Henderson was only denied by a Ferrari goal-line clearance, then the move continued, Consigli making an acrobatic save on Nicolas Haas.
It was wide open, Traore drilling wide on the counter, while Gianluca Scamacca failed to make the most of the great work from Maxime Lopez.
Jeremy Toljan flashed a ball across the six-yard box, with Gregoire Defrel sliding in a second too late, while Vicario denied Jeremie Boga at the near post.
The host were eventually made to regret wasting all those opportunities, because Vlad Chiriches went through the back of Patrick Cutrone for an inevitable penalty. Pinamonti converted for Empoli to equalise.
The regrets became even stronger when Empoli snatched victory practically with the last kick of the game. Henderson rolled across from the left and substitute Szymon Zurkowski smashed it first time off the underside of the bar, goal-line technology confirming it had completely crossed over.
It was a reverse of fortunes for Sassuolo, who had beaten Juventus with the last kick in the midweek round and suffered the same fate here.
Sassuolo 1-2 Empoli
Tonelli og 43 (S), Pinamonti pen 83 (E), Zurkowski 92 (E)