Wigan took an early lead through Chris Ashton's unconverted try but Quins hit back through Paul Sykes' try and he added two goals to put them 8-4 up.
Trent Barrett went over for Wigan just after the hour mark to make it 16-8 but Sykes' fifth goal wrapped things up.
Wigan boss Brian Noble:
"We have to find an answer because one week we are getting Jekyll and one week we are getting Hyde.
"It's frustrating to have some people setting themselves really high standards one week but not living up to them the next.
"I am disappointed that we can't get an element of consistency in our game."
Harlequins: Melling, Wells, Sykes, T Smith, Clubb, Orr, McLinden, Temata, Randall, Mills, Gafa, Hopkins, Hill.
Replacements: Rinaldi, Worrincy, Mbu, Walsh.
Wigan: Ashton, Calderwood, Bailey, Vaealiki, Richards, Barrett, Leuluai, Fielden, Millard, Paleaaesina, Hock, Fletcher, O'Loughlin.
Replacements: Higham, Hansen, O'Carroll, Prescott.
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