Santos' men have six points from three Euro 2016 qualifying matches after Friday's 1-0 win over Armenia, but revert to friendly status to take on the Messi-led World Cup finalists.
While the Greek tactician conceded Messi was Argentina's main man going forward, he said he would be plotting to defeat the South Americans - not just the Barcelona superstar.
"That's how Argentina plays. Their coach [Gerardo Martino] already said that position is the most indicated to Messi," Santos said.
"If he played for the other side you would have asked me if my centrals would focus on Messi there.
"We have to worry about what Argentina does.
"Obviously, if Argentina have a player with that kind of quality it makes difference but Argentina is a very strong team with so many great players, so we have to pay attention to all of Argentina's movements."
Santos also weighed into the 'Messi v Ronaldo' ongoing debate, claiming the Real Madrid man has been in better form recently.
"I voted for Cristiano," Santos said of the Ballon d'Or voting.
"I think this season he was the best player in the world. But of course you always have to consider Messi because he's a fabulous player.
"I've already said Messi and Cristiano Ronaldo are two geniuses. But, this year, I think Cristiano was better."
Portuguese defender Ricardo Carvalho said the Argentines would provide a stern test for the Euro 2016 aspirants, and echoed Santos' claims they were all about a team performance - and not a reliance on Ronaldo.
Ronaldo has scored Portugal's only two goals in Euro qualifying so far, in two 1-0 wins.
"I think it's natural the press talks about Cristiano and Messi above Portugal against Argentina, but it's a good test for us," the Monaco stopper said.
"It's important to us and also to Cristiano play against big national teams and, fortunately, tomorrow [Tuesday] we'll have the pleasure to play against Argentina.
"More important than looking at one player is that we look ourselves as a team. We play as a block, we defend well and we will try to attack with quality when we have to."
