The USA fixture was the Golden Eaglets' first match of Group A which also includes the hosts Chile and Croatia.
Goals from Chukwudi Agor and Victor Osimhen handed the reigning champions the victory in Santiago.
Both goals came in the second half with Agor scoring on 50 minutes, and Osimhen adding a second 11 minutes later.
Nigeria also had a man advantage late in the match after USA's Auston Trusty was sent off in the 87th minute for a bad challenge.
Nigeria's coach, Emmanuel Amuneke was pleased with his side's performance.
"Considering it was the first match, I think it was a good game," he told Fifa's website.
"Besides the three points, which are very important, I also liked that we kept our heads even when we could not get things going," Emmanuel Amuneke added.
The reigning champions are top of Group A after the first round of matches following a 1-1 draw between Chile and Croatia.
Guinea began their Group B campaign with a hard fought 1-1 draw against England in Coquimbo.
The first half was goal-less although England's Marcus Edwards missed a penalty to deny his team a lead going into the break.
But England did seize the advantage in the second half through Kaylen Hinds after 61 minutes.
Guinea fought back to secure a point with an equaliser from Naby Bangoura 15 minutes later.
Korea Republic top Group B after a shock 1-0 win over three-times former winners Brazil.
Four African nations in total will feature at the Fifa Under-17 World Cup.
Nigeria and Guinea are joined by the current African champions Mali and South Africa.
Nigeria began the defence of their Fifa Under-17 World Cup crown with a 2-0 victory over USA on Saturday, as Guinea opened with a 1-1 draw against England.