Luciano Spalletti – whose position continues to be the subject of intense scrutiny – said earlier in the week that he wanted his players to treat the game as a "cup final" and they duly responded in the early stages, with only the brilliance of Empoli goalkeeper Bartlomiej Dragowski preventing them from putting the game to bed before half-time.
Keita Balde Diao's introduction at the interval proved a masterstroke as the 24-year-old superbly whipped past Dragowski from outside the penalty area to open the scoring.
Empoli took full advantage of Mauro Icardi's penalty miss soon after, though, to level in the 76th minute through Hamed Junior Traore.
However, Nainggolan slotted home nine minutes from time and a hectic finish saw Inter defender Danilo D'Ambrosio clear against his own crossbar before Marcelo Brozovic had a goal ruled out by VAR after Keita fouled Dragowski – rushing back to his own goal from a corner – to earn the forward a second yellow and consequent red card.
Inter finish a point above city rivals AC Milan in fourth, while Empoli make an immediate return to Serie B after Genoa's 0-0 draw away at Fiorentina.
Inter started on the front foot and were denied an opener after 10 minutes when Dragowski superbly tipped Ivan Perisic's 20-yard drive wide.
Keita was introduced at the break and the Senegal international made an immediate impact, curling into Dragowski's bottom-right corner from 20 yards in the 51st minute.
Icardi then had the chance to double Inter's advantage shortly after the hour-mark when referee Luca Banti – after a VAR review – deemed Dragowski to have brought him down inside the penalty area. The Argentina international's weak spot-kick was comfortably kept out by the Empoli goalkeeper, however.
The visitors took full advantage of that reprieve when Traore ghosted in at the back post to tap in Salih Ucan's low cross.
Inter came roaring back, though, and Nainggolan slotted into an empty net after Matias Vecino's shot had cannoned back off the post.
Empoli came agonisingly close to denying Inter – and preserving their Serie A status – in the closing stages, D'Ambrosio striking his own crossbar from just five yards out and Samir Handanovic thwarting Ucan from close range.
Brozovic thought he had scored a third deep into stoppage time but his effort from the halfway line was ruled out by VAR after Keita had pulled down the backtracking Dragowski.
The Inter forward received a second yellow card for the offence, while Empoli's substitute goalkeeper Filippo Perucchini was dismissed for his remonstrations from the bench, but it will do little to detract from a precious win for the Nerazzurri.
Inter stumble into the Champions League
With Antonio Conte apparently waiting in the wings to claim the Inter throne, Spalletti might not be in the mood to celebrate his side's Champions League qualification. In truth, they should have wrapped up a top-four finish weeks ago but a run of one win in their five previous games prior to the visit of Empoli means their qualification for European football's showpiece event feels more than a little underwhelming.
