Inter put seven past helpless Sassuolo
Rodrigo Palacio, Saphir Taider, Ricardo Alvarez and Estaban Cambiasso also scored for Inter, and defender Raffaele Puccino added an own goal.
Milito, who came on in the 54th, had been out since injuring his left knee in February.
Inter moved one point ahead of Napoli and Roma, which play later.
Napoli's perfect start will be put to the test at the San Siro against AC Milan. Roma, which also won its opening three matches, meets Lazio in the capital's derby. Also, two-time defending champion Juventus hosts promoted Hellas Verona.
The emphatic victory for Inter comes amid news that Indonesian businessman Erick Thohir is closing in on a takeover of the club.
New Inter coach Walter Mazzarri has made an immediate impact with the Nerazzurri, which drew 1-1 with Juventus last week after winning its first two matches.
Palacio put Inter ahead seven minutes in following a cross from Yuto Nagatomo, Taider scored his first goal with Inter in the 23rd by redirecting a rebound from Palacio and Puccino made it 3-0 in the 33rd when he tried to beat Taider to the ball but ended up putting it in his own net instead.
Alvarez made it 4-0 with a rebound of a shot from Palacio in the 53rd. Milito replaced Palacio a minute later and needed just nine minutes to score, taking a cross from Alvarez and redirecting it in from close range.
Cambiasso found the target with a long shot in the 75th and Milito scored again in the 83rd after taking a pass from Fredy Guarin.