Walter Mazzarri's side were dominant from start to finish in Sassuolo, with Rodrigo Palacio setting the tone in the seventh minute with the game's first goal as Inter recorded their biggest away victory in the Italian top flight.
Saphir Taider's strike and a Raffaele Pucino own goal gave Inter a 3-0 lead at the break before Diego Milito struck twice in the second half, and Ricky Alvarez and Esteban Cambiasso also scored.
Milito's first goal was widely celebrated, with the Uruguayan forward netting in his comeback appearance after a serious knee injury.
The 34-year-old, who had not played for Inter in over seven months, came off the bench in the second half and produced a smart finish before Cambiasso added a 20-yard strike.
And there was still time for Milito to grab a second, as he tapped in Fredy Guarin's assist to cap off a sensational victory.
Inter's position at the top of the table may only last a matter of hours but their fans will enjoy it, having endured a disappointing campaign last season, finishing ninth.
Mazzarri's new-look Inter have conceded just one goal in their five competitive matches this season, and they have now scored 17 goals.
Inter were unchanged from the team that drew 1-1 with Juventus last week, while rock-bottom Sassuolo – who had lost all three of their Serie A fixtures this season – shuffled their pack.
They made three changes, including the recall of former Udinese striker Antonio Floro Flores, but were behind inside the first 10 minutes.
After a spell of Inter pressure that saw them win multiple early corners, Japan international Yuto Nagatomo burst down the left flank before producing a superb cross for Palacio to tap in.
Jonathan had an effort well blocked for Inter as they pressed for a second, before Algerian Taider found himself in the right place at the right time.
He followed in a saved Palacio effort to score easily past Alberto Pomini, and the goals kept coming for the visitors.
Their third, scored in the 33rd minute, made a mockery of Sassuolo's defence as a long ball from the terrific Guarin bounced in between Jonathan Rossini and Pucino.
With Haider lurking, Pucino panicked and steered a header over a stranded Pomini as Inter's travelling fans celebrated again.
Jonathan almost scored a fourth for Inter, but his effort was well saved, while Floro Flores had two opportunities before the break, the second of which forced a smart stop from Samir Handanovic.
Alvarez was also a constant threat for Inter and after going close early in the second half, he got himself on the scoresheet, following in another saved Palacio effort, before Milito enjoyed his moment in the sun in the 64th minute.
Alvarez was the provider, getting to the byline before cutting back for Milito, and Cambiasso got in on the act with 15 minutes remaining, scoring an excellent curling finish on his left foot.
Milito wrapped up the win with an easy second, seven minutes from time, as Inter scored more than six goals in a league match for the first time since 1996.
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