With top scorer Romelu Lukaku benched for the opening hour, the Nerazzurri were toothless in attack and squandered an early opportunity to take the lead as Alexis Sanchez missed a penalty.
Sampdoria had no such trouble and went ahead with a spot kick of their own through Inter loanee Antonio Candreva midway through the first half. Shortly after, another familiar face heaped further misery on the Nerazzurri, as their former winger Keita Balde tucked away a low cross.
Despite Stefan De Vrij’s header in the second half, Inter were unable to salvage anything and fell to just a second defeat of the season.
Inter had the first chance to break the deadlock as Sanchez spun in the box and teed up Ashley Young, with the Englishman’s side-footed effort forcing Emil Audero to tip over the bar. From the resulting corner, Milan Skriniar found space but sliced just inches wide.
However, a VAR check showed that the ball had clipped Morten Thorsby’s outstretched hand en route to falling to Skriniar and the Nerazzurri were awarded a penalty. Sanchez stepped up but his weak effort was parried by Audero, before Young blasted the follow up against the post.
At the other end, Sampdoria began to threaten and Lorenzo Tonelli’s header came off the crossbar from a deep Candreva freekick.
With just 20 minutes gone the hosts were awarded a penalty of their own, courtesy of a VAR review. After Adrien Silva’s low drive was deflected behind, Tonelli met the incoming corner and nodded against Nicolo Barella’s arm, despite the midfielder’s protestations. Candreva made no mistake from the spot against his parent club, sending Samir Handanovic the wrong way.
Sampdoria were in the ascendancy and doubled their lead late in the first half through another former Inter man. Mikkel Damsgaard broke forward from midfield and knocked the ball round Alessandro Bastoni to burst into the box and deliver a pinpoint low cross for Balde to tuck away.
Inter made a determined start to the second half and Lautaro Martinez came close with a clever backward header, whilst Sanchez miscued an effort from a dangerous Achraf Hakimi cross.
Sampdoria remained a danger as Candreva led a rapid counterattack and squared the ball to Jakub Jankto, but his low shot was tipped away by Handanovic.
Midway through the second half Inter halved the deficit through De Vrij, as the centre-back rose above Omar Colley to head in from a corner.
The Nerazzurri continued to push forward and substitute Lukaku forced an excellent low save from inside the box, as Inter began to dominate. Meanwhile, Ivan Perisic came within inches of an equaliser from a corner at the back post.
Inter’s best opportunities were coming from set-pieces as Perisic again headed wide in space from a corner, whilst Christian Eriksen squandered a late freekick from the edge of the box.
Sampdoria held firm however to condemn Inter to just a second league defeat of the season and prevent the Nerazzurri from moving top of Serie A.