Antonio Candreva and Keita Balde were on target against their former club as Inter's eight-match winning run in Serie A ground to a halt in a 2-1 defeat at Sampdoria.
The Nerazzurri were aiming to go top, at least temporarily, and Alexis Sanchez saw an early penalty saved at the Luigi Ferraris.
Another VAR check led to Candreva opening the scoring from the spot and Keita – on loan at Sampdoria from Monaco – doubled the hosts' lead in an enthralling first half.
Stefan de Vrij finally headed wasteful Inter onto the scoreboard after 65 minutes, but Antonio Conte's side failed to find and a leveller and remain second, one point adrift of Milan.
In a breathless opening, Emil Audero foiled Ashley Young's whipped shot and Milan Skriniar skewed wide from the same corner that saw Morten Thorsby pinged for handball after VAR's intervention.
Audero kept out Sanchez's penalty and Young smashed the rebound against the post, while Lorenzo Tonelli's looping header for Sampdoria hit the crossbar soon after.
Candreva succeeded where Sanchez failed after 23 minutes, firing into the left of the goal after VAR spotted Nicolo Barella had handled a Tonelli header.
Things worsened for Inter when Keita swept home Mikkel Damsgaard's low right-wing centre seven minutes before the break.
Sanchez was denied by Audero again and Lautaro Martinez wastefully headed wide, before the former followed suit in similar style after the break.
Inter finally responded when De Vrij headed home Marcelo Brozovic's corner with 25 minutes left and substitute Romelu Lukaku saw a powerful downward header brilliantly stopped by Audero.
Ivan Perisic was twice off target with headers either side of Martinez testing Audero at his near post but Inter were frustrated in their endeavours.
What does it mean? Conte's men pass up great opportunity
With unbeaten league leaders Milan scheduled to face Juve later on Wednesday, Inter had the chance to leapfrog their neighbours - at least temporarily.
But Conte's side were wasteful when chasing a ninth straight league win, with only seven of their 25 shots finding the target. On another day this could have been a cake walk for the visitors, but the reality is their 11-match unbeaten run comes to an end.
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As well as his penalty, Candreva had four key passes and completed 21 of 27 passes (77.8 per cent). Keita stretched Inter's defence and completed each of his 10 passes.
Martinez and Sanchez misfire
Martinez was the catalyst for the 6-2 battering of Crotone on Sunday, scoring a hat-trick on that occasion. But here, in a game where Lukaku (thigh) was only fit enough to play the final half an hour, the Argentine striker was uncharacteristically wasteful.
Only one of his seven efforts were on target while his passing accuracy was just 44 per cent in an underwhelming showing.
Sanchez had two shots on target – albeit one was his missed penalty – but he too was guilty of misfiring, especially with a poor header early in the second half.
Key Opta facts
- Sampdoria have won a game against Inter in Serie A for the first time since April 2017 - six defeats in a row conceding an average of 2.7 goals per game since then.
- Inter have lost an away game in Serie A for the first time since the defeat against Juventus in March 2020, in their last match before the lockdown.
- Sampdoria have scored in 16 consecutive home games in Serie A for the first time since October 1994 (16).
- Keita has found the net for consecutive games in Serie A for the first time since December 2018, doing so with Inter.
Inter face a tricky trip to Roma on Sunday, a day before Sampdoria visit lowly Spezia.