The fixtures are set to serve as FIFA World Cup warm-up matches for the two South American nations, but O'Neill will use the ties to experiment with new faces.
Portsmouth goalkeeper Trevor Carson has been part of the senior squad in the past, but is yet to win a full cap for his country, while Liverpool defender Ryan McLaughlin is rewarded for his displays during a loan spell at Barnsley at the back end of the season.
Doncaster Rovers' Luke McCullough and Liam Donnelly of Fulham could also make their first appearances in the Northern Irish back line, while Dundee United's Paul Paton - fresh from suffering a 2-0 defeat to St Johnstone in the Scottish Cup Final - is named among the midfielders.
The team head to South America without Manchester United defender Jonny Evans, West Brom duo Gareth McAuley and Chris Brunt, Palermo's Kyle Lafferty and Hull City's Alex Bruce, who was substituted in the second half of his side's FA Cup final defeat to Arsenal on Saturday.
O'Neill's charges take on Uruguay in Montevideo on May 30, before travelling to Valparaiso to face Chile on June 4.
