However, Agger made amends 10 minutes later as he drove forward from defence, exchanged passes with Andrea Dossena and cut the ball back for Kuyt to fire home.
Suddenly the confidence returned to Liverpool's play and Kuyt nearly grabbed a second as he unleashed a rasping shot from 20 yards that Chris Kirkland somehow managed to tip onto the crossbar.
But they were stung on the stroke of half-time as Zaki met Valencia's cross with a brilliant acrobatic effort that gave Reina no chance.
After the break Liverpool started to turn the screw and Lee Cattermole was on hand to clear Agger's header back across goal with Keane lurking at the far post.
Kuyt was then denied again by Kirkland from six yards as the home side struggled to break Wigan's resistance.
Bruce incensed by sending off
However, when Valencia was given his marching orders, the game swung in Liverpool's favour.
The Ecuador international was shown a yellow card for failing to retreat 10 yards as Gerrard lined up a free-kick and just a minute later he was on his way down the tunnel for a reckless tackle on Xabi Alonso.
Liverpool immediately looked to make their man advantage count and Alonso saw his shot from 25 yards deflected wide by Titus Bramble, before Riera drew them level with a right-footed shot from 20 yards.
It was the Spaniard's first goal in a Liverpool shirt, but Liverpool were not done yet.
They sensed victory as Wigan began to tire and Kuyt sealed the win with his fourth goal in three games.
He met Jermaine Pennant's pin-point cross with a flying volley that hit the ground before flying over the despairing dive of Kirkland.
Liverpool manager Rafael Benitez:
"I think that we were attacking, controlling and creating chances so we were in control of the second half.
"We didn't start well and they started really well.
"After conceding the goal the team was a little bit nervous but when we scored the first goal, we were again in the game and were controlling.
"We then concede the second goal when we were playing better."
Wigan manager Steve Bruce on Antonio Valencia's sending off:
"Every decision that was contentious was given to Liverpool.
"Every little decision went their way. The first yellow card, he doesn't deserve a yellow card, the second one is arguable.
"That was the decisive moment in the match because up until then we were coping admirably and were arguably the best team."
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