Inter were already leading the Serie A newcomers 4-0 when Milito, 34, came on for his first game since suffering a knee ligament damage in a Europa League match against Cluj in February.
Milito needed only nine minutes to make his mark as he turned in a cross from fellow Argentine Ricky Alvarez in the 63rd minute.
His second goal 20 minutes later was equally straightforward as he tapped in Fredy Guarin's cross from close range after Sassuolo, who have lost all four opening games in an unhappy top flight debut, were again caught on the counter-attack.
Five of the Inter goals came from Argentines with Rodrigo Palacio, Alvarez and Esteban Cambiasso also on target.
Palacio opened the flood gates in the seventh minute when he was left unmarked to tap in Yuto Nagatomo's pass after seven minutes.
Algeria forward Saphir Taider put Inter further head when he snapped up a rebound in the 23rd minute after Palacio's first effort was saved, the 21-year-old's first goal since his move from Bologna in the close season.
Sassuolo's nightmare continued when Raffaele Pucino, making his Serie A debut after replacing the injured Marcello Gazzola after 14 minutes, headed Guarin's cross into his own net just after the half hour.
Alvarez added the fourth in the 53rd minute while Cambiasso scored the best goal of the game when he curled in a 20-metre effort, sandwiched between Milito's goals.
Inter, unbeaten under new coach Walter Mazzarri, have taken 10 points from their opening four games.
- Sports & Recreation
- Rodrigo Palacio
- Fredy Guarin
- Esteban Cambiasso