The Spanish-born Senegalese international met Sime Vrsaljko's low cross with a first-time shot on the turn in the 72nd minute as Inter reached the halfway mark of the championship with 39 points, 14 behind leaders Juventus.
It was Inter's third 1-0 win in their last four league matches, although they performed in fits and starts and needed a good save by Samir Handanovic from Miha Zajc to prevent Empoli going ahead at the start of the second half.
Promoted Empoli's fourth successive league defeat left them 17th in the 20-team table with 16 points, one place above the relegation zone.
Nainggolan started on the bench and came on in the second half and coach Luciano Spalletti said that the Belgian sometimes put "other things" in front of football.
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"I brought him on because I thought he could give us some help and it was the right decision," Spalletti told reporters.
"We want what is good for him, he's a sensitive lad and he has all the right qualities. Sometimes, he is attracted by other things and if someone puts too many other things in front of football, they don't win."
The shaven-headed coach was happy with the way his team approached the game, especially after they were held 1-1 at table-propping Chievo in their last away match.
"These are games where you can easily slip up if you don’t have the right mentality," he said. "We didn’t play too well in the first period, but we did better in the second half due to their energy levels dropping off."
(Writing by Brian Homewood; Editing by Clare Fallon and Christian Radnedge)
