Balotelli, who had earlier headed a glorious chance wide of the target, broke the deadlock in the 69th minute as he seized on a fumble from Ali Al Habsi following Gareth Barry's shot to rifle home at the second attempt.
And substitute Milner, who had only joined the fray just before the hour mark, made sure of the victory three minutes later as he arrowed an unstoppable effort into the top corner of the net from outside the area after Barry's square ball, only for the England midfielder's goalscoring cameo came to an unhappy end soon after as he limped out of the action and straight down the tunnel.
Aroune Kone had missed a great opportunity to give the home side the lead when the game was still locked at 0-0 and Wigan will feel the final score was harsh as they more than matched the visitors for long periods with Roberto Mancini's men looking short of inspiration and penetration until the breakthrough.
Wigan made two enforced changes as Adrian Lopez and Franco di Santo came in for Shaun Maloney and Ivan Ramis, while Balotelli returned to the City starting line-up for the first time in six matches.
Maicon and Javi Garcia also played as Mancini made three changes with Aleksandar Kolarov, Milner and Edin Dzeko dropping to the bench. Joleon Lescott was again left out of the squad.
There were early chances at both ends, with Kone firing straight at Joe Hart after being released by Di Santo, while Maicon lashed wide of Al Habsi's goal after rampaging from full-back into the Wigan area and being found by David Silva.
There was a moment of concern for City as Maicon went down in some distress after taking a ball in the throat from Di Santo, but the defender was able to continue after treatment and was a continual threat with his forward runs.
City were rarely testing Al Habsi and were grateful to see Vincent Kompany block Jean Beausejour's shot before Kone's near-post header after a superb surge down the right flank from Ronnie Stam went over the bar.
Jordi Gomez felt he should have a had a penalty as he went down under a challenge from behind by Pablo Zabaleta on the edge of the area as half-time approached but Mark Halsey was not interested, with the Wigan man booked soon after for a nasty and late challenge on Barry.
City then had an equally strong claim for a spot-kick waved away early in the second period as Stam was pulling Barry's shirt from his back at the far post as they battled for Yaya Toure's cross, but again referee Halsey gave nothing.
Balotelli and Kone then traded examples of how not to head the ball after being found by Maicon and James McCarthy, respectively, before the Italy international justified his place in the starting XI by breaking the deadlock and then celebrating with substitute Carlos Tevez, with Milner's rocket making the game safe soon after.