Inter's third successive win in the group kept them top with nine points from four games and within touching distance of the last 16 as they put their dismal domestic form behind them.
Milito's fellow Argentine Walter Samuel opened the scoring for the ageing Serie A strugglers, fielding a team with a Champions League record average age of nearly 32, but Tulio de Melo made the hosts suffer by pulling one back in the 83rd minute.
Milito, struggling to rediscover the form of two seasons ago when he was pivotal in Inter's treble campaign under Jose Mourinho, had the half-full San Siro groaning in disbelief immediately after the restart of the game.
Wesley Sneijder took a free-kick on the left and a poorly-executed Lille offside trap left Dejan Stankovic and Milito alone in front of goal.
Stankovic laid the ball into Milito's path and he somehow volleyed over the open goal from six metres.
The Argentine was the villain again shortly afterwards when he broke clear but shot weakly at Mickael Landreau with Stankovic and Mauro Zarate both free and shouting for the ball.
All was forgiven, however, in the 65th minute when he flicked the ball into the net for his first Champions League goal of the season after captain Javier Zanetti, 38, burst into the Lille area.
"I think Milito was the symbol of the match," coach Claudio Ranieri told reporters.
"He missed a couple of chances but he kept looking for the ball and in the end he scored.
"I think the help and encouragement from the supporters for Milito and for the team showed that they like this team."
ROSE UNMARKED
The 2010 Champions League winners are 17th in Serie A, having won only twice in nine outings.
They have also been beaten in their last three home Champions League outings but were quick out of the blocks against Lille when Cristian Chivu sent Milito away and he lobbed against the bar.
Zarate, one of only three under-30s in the Inter line-up, nearly put the hosts ahead in the 18th minute when his shot squeezed under Landreau and slipped wide.
From the resulting corner, Samuel rose unmarked to head Inter in front.
Lille, with 20-year-old Belgian Eden Hazard pulling the strings in midfield, had plenty of possession but rarely threatened stand-in goalkeeper Luca Castellazzi.
The visitors, who stayed bottom of the group with two points, kept plugging away after Milito's goal and Hazard nearly pulled one back when he had a curling free-kick saved by Castellazzi.
Inter were never entirely convincing and gave a goal away in the 83rd minute when a dreadful mistake by Brazil defender Lucio let in his less well-known compatriot Tulio de Melo to dink the ball delicately over Castellazzi.
