The South American trio fired Andrea Stramaccioni's charges to glory ahead of Saturday's Derby d'Italia, in spite of their visitors taking a shock early lead
Goals from Diego Milito, Rodrigo Palacio and Fredy Guarin settled matters, cancelling out Gianni Munari's first-half effort to go second in the league, right behind this weekend's opponents Juventus.
Coach Andrea Stramaccioni rotated his men ahead of Saturday's Derby d'Italia, with Gaby Mudingayi and Palacio reprising their roles in the starting line-up. Sampdoria meanwhile had Marcelo Estigarribia and Roberto Soriano acting in support of Eder.
Although the new San Siro turf held up better under the pre-match deluge of rain, play struggled to truly get going, as the ball constantly got bogged down in puddles across the pitch. With neither side able to gain the upper hand in the opening minutes, it was Palacio who had the first chance of the night, shooting high over Sergio Moya's bar.
Milito was proving particularly lively, and showed good strength in shrugging off the challenges of two Sampdoria defenders before hitting a potshot straight at Moya. Although the Nerazzurri were beginning to gain the upper hand and stamp their authority on the game after a Walter Samuel header went wide, it was Ciro Ferrara's side who took a shock lead.
Andrea Ranocchia was guilty of getting into a tangle with Samuel as both stoppers scrambled to clear a loose ball from a free-kick in the 20th minute, and the misunderstanding allowed Munari, who was on hand, to sweep home past a stranded Samir Handanovic.
The goal appeared to galvanise the Blucerchiati, who enjoyed a solid helping of possession over the following 10 minutes. Apart from Guarin lashing a powerful effort just wide, and Palacio sending a teasing cross across the face of Sampdoria's goal, Inter were restricted to negligible half-chances for the most part, and entered the break desperately short of ideas.
Esteban Cambiasso came on for the second period in place of Mudingayi, as Stramaccioni placed his chips on the 32-year-old to supply his isolated forward line with more ammunition. The Argentine almost made an immediate impact to tee up compatriot Palacio outside the area, but the former Genoa forward made an awkward connection, and the ball trickled out of play.
It was Sampdoria who conspired to undo all their good work to that point however, as Andrea Costa gave away a penalty and saw red for a professional foul on Milito. The veteran striker picked himself up and placed the spot-kick beyond the reach of Moya, cannoning in off the post.
With the belated equaliser, Inter poured forward with renewed fervour, urged on by the home support, who had lost their voice till then. However, It was Palacio yet again to showcase his profligate side, heading high over after a cross from Javier Zanetti. The 30-year-old then failed to latch onto a through-ball from Guarin, with the forward looking visibly more frustrated on each occasion.
Nevertheless, it was third time lucky for the hitman in the 69th minute, who's perseverance eventually paid off. Antonio Cassano initiated a lightning-fast break into Sampdoria's half, and this time, Palacio made no mistake from close range. Visibly boosted after adding to his tally, he followed his goal up by blasting narrowly wide from a narrow angle, with Sampdoria's custodian well and truly beaten.
Guarin rounded off the rout with a long-distance curler from the edge of the box, as the clock winded down. Yuto Nagatomo fed Cassano, who spun to find the midfielder. Samp coach Ferrara was handed his marching orders shortly after, with the former Italy international thought to be protesting a suspected offside in the goal's build-up too vehemently.
Proceedings were far from over however, as Eder set up a nail-biting finish in the last-minute of stoppage time, finishing off an intricate move. It was to prove too little, too late however, as the referee called time on the match.
Following Napoli's defeat at Atalanta, it is Inter who secure themselves a vital boost ahead of their crunch encounter against Juventus on Saturday. Meanwhile, Sampdoria's slump continues, as they now find themselves in mid-table after suffering their fifth consecutive defeat.