The West Brom winger is set to win his 50th cap in the game in New Jersey.
O'Neill has left several senior players at home to rest ahead of the World Cup qualifier against Austria on 11 June, but McClean asked to be involved.
"I think it would be worthwhile doing that. If he starts the game I'm sure he will be captain," O'Neill said.
With no specialist left back in the travelling party, McClean could be handed a different role.
"We could possibly play three centre-halves and two wing-backs, James has done that before," O'Neill said.
"It gives us the chance for a bit of experimentation.
"Most of the boys who are playing in the Premier League will join up with us after the game in the US, but James wanted to come out. He has got a great attitude."
Shane Duffy could get the chance to blow away his end-of-season frustration in the United States after escaping injury in a road accident.
The 25-year-old Brighton defender missed the final 11 games of his club's promotion-winning campaign after fracturing a metatarsal in March, but was involved in the Republic's training camp in Cork last week.
The vehicle in which he and Leeds midfielder Eunan O'Kane were travelling in on Sunday was involved in an accident on the way to the team hotel in Dublin.
O'Neill said the accident was nothing serious, adding: "I don't think there's any more to report, other than that the two lads are OK."
The Republic host Uruguay - who will be without Barcelona striker Luis Suarez - in Dublin on 4 June before the World Cup qualifier against Austria at the Aviva Stadium a week later.
Martin O'Neill has indicated he will hand James McClean the captain's armband in the Republic of Ireland's friendly against Mexico on Friday.