The USA had a promising start to the game with Christian Pulisic orchestrating from the left side, but well before the first half hit the halfway point, Nigeria, a record four-time winner of the U-17 World Cup, found its stride and dominated for the rest of the game.
The Golden Eaglets outshot the Americans 19-5 while the USA failed to force a save from Nigeria goalkeeper Akpan Udoh.
Coach Richie Williams' team did survive the onslaught until the 50th minute, when defender Austin Trusty botched his attempt to clear a cross from John Lazarus, setting up a close-range blast into the net from Chukwudi Agor.
Eleven minutes later, Agor headed an up-the-middle U.S. goal kick to Victor Osimhen, who shook off a challenge from U.S. captain Hugo Arellano before stroking the ball past U.S. keeper Will Pulisic.
Trusty, the only field player added to the squad that Williams used at the qualifying tournament in March, was ejected in the 87th minute.
A clear title favorite based on history and Saturday's performance, Nigeria was denied a bigger win by U.S. keeper Pulisic, giving the USA a silver lining of not entering its final two Group A games with a worse goal differential. The top two finishers and best four third-place finishers of the six groups earn second-round passage.
In the other Group A opener, host Chile settled for a 1-1 tie with Croatia, the USA's next opponent Tuesday (4 p.m. ET, FOX Sports 2 and NBC Universo).
Oct. 17 in Santiago
Nigeria 2 USA 0. Goals: Agor 50, Osimhen (Agor) 61.
Nigeria -- Udoh; Lazarus, Enogela, Zakari, Bamgboye (Chukwueze, 81); Osimhen (Okwonkwo, 90+3), Nwakali, Agor (Michael, 61), Ikwu; Anumudu, Ebere.
USA -- Pulisic; Olosunde (Adams, 67), Trusty, Arellano, Nelson; Zendejas, Calvillo, Perez; Wright (de la Torre, 64), Gallardo (da Silva, 83), Pulisic.
Red card: Trusty (USA) 87.
Referee: Deniz Aytekin (GER)