The friendly match in Valletta comes ahead of a World Cup qualification double header with Russia and Israel next month - and with striker Kyle Lafferty and defender Chris Baird both suspended for those games, the squad is expected to have a more youthful look than usual.
Billy McKay, Adam McGurk, Will Grigg and Josh Magennis are all waiting in the wings, and Inverness' McKay - the Scottish Premier League's top scorer this season - looks to be in line for the vacant position up front.
Meanwhile fellow uncapped players McGurk, goalkeeper Gerard Doherty and defender Alex Bruce will all hope to play a role at the Ta'qali National Stadium later.
Speaking after a training session on Tuesday evening, O'Neill said: "One pleasing aspect of this game is that gives me the opportunity to bring some of the younger players through and to see how integrate with the more experienced members of the panel.
"With regard to the game tomorrow, make no mistake that Malta will be well drilled and we will be giving them the respect they deserve but I'm confident we'll be able to take a number of positives forward into next month's double header with Russia and Israel."
The friendly in Malta will also be O'Neill's eighth attempt at getting a win as NI manager.
Results under his tenure thus far have been a mixed bag, ranging from a hard-earned draw in Portugal, to underwhelming draws with Luxembourg and Azerbaijan.
But team captain Steven Davis insists progress has been made under the former Shamrock Rovers boss, saying: "There's a good feeling about the squad, everybody enjoys meeting up and everybody gets on well.
"It's nice to get a break away from your club as well. It's nice to see some younger players coming into the squad and getting their chance to stake a claim.
"The performances have been really good. Obviously we try to get the ball down and play, create chances and press teams as well. It's just disappointing the results haven't matched the performances.
"But I think we've seen progression in each game we've had so far. We're in a really difficult group, we knew that at the start. We could quite easily be sitting here on seven points but we are where we are and we've just got to concentrate on keeping moving forward."
The game in Malta kicks off at 6.30pm.