The Internacional forward proved decisive as he guided la Celeste to a vital victory over the Super Eagles in his 100th appearance for the national team
The South Americans started impressively and Diego Lugano, who will miss the next game after picking up his second yellow card of the tournament, soon broke the deadlock.
John Obi Mikel equalised with a fine finish but in the second half Diego Forlan marked his 100th cap for the national team with the winning goal, as Stephen Keshi's men paid the price for failing to test Fernando Muslera for much of the game.
Uruguay began brightly but were unable to take control of the game during the early stages as Nigeria proved a threat on the counterattack.
La Celeste lost momentum but still opened the scoring in the 19th minute. Forlan's deflected cross was unintentionally dummied by Edinson Cavani at the near post and an unmarked Lugano scuffed the ball into the back of the net.
Some last-ditch defending from Maxi Pereira stopped Brown Ideye from getting a shot away on goal moments later while, at the other end, Forlan was unable to squeeze a Luis Suarez cross in at the near post with 26 minutes played.
The game had gone flat after Oscar Tabarez's side had taken the lead, but the crowd were sparked back into life eight minutes before the break when the Super Eagles restored parity.
Ideye fed Mikel at the top of the box and the Chelsea midfielder jinked past the static Lugano and bent a fine left-footed finish into the top corner.
Nigeria narrowly missed out on taking an advantage into the interval as a scrambling Muslera did brilliantly to stop Diego Godin from putting through his own goal with a looping header in first-half stoppage time.
The African champions picked up where they left off following the restart but it was Uruguay who struck next with 51 minutes on the clock.
Suarez and Cavani combined to set up Forlan on the left of the area and he capped a century of appearances for La Celeste with an unstoppable, first-time finish beating Vincent Enyeama at his near post.
The goal came as a blow to the Super Eagles and the South Americans made it difficult for Keshi's men to break them down by bolstering their numbers behind the ball when not in possession.
With 20 minutes remaining Cavani wasted a glorious opportunity to wrap up the three points as, after springing the offside trap, he snatched at the ball and sliced his effort well off target.
The Napoli striker then ailed to hit the target again with a free header shortly after but Tabarez's team retained their single-goal advantage up to the final whistle.
Although they stay in third position, Uruguay will have the upper hand heading into the final round of fixtures in Group B as they take on Tahiti while Nigeria will face world champions Spain.