Manchester's Old Trafford will host the fixture, meaning a return to the city for former United star Ronaldo, which is highly anticipated despite its friendly status.
Given the complete dominance of Messi and Ronaldo in world football, you would be hard pressed to find a football fan who would argue anyone else belongs in the top two current players - as has been shown by the FIFA Ballon d'Or's recent history.
Either Barcelona's Messi or Real Madrid's Ronaldo has won the prestigious award for the last six years and although debates over who is the best are likely to rage for decades to come, there is no doubting their stardom.
Both sides come into the match off the back of victories - Portugal's coming in a competitive match on Friday.
Fittingly, Ronaldo scored the only goal of their 1-0 Euro 2016 qualifying success against Armenia - a strike that saw him become the highest goalscorer in European Championship history.
It was a similar tale in Denmark last month - Ronaldo giving Portugal a 1-0 win as they bounced back from a shock home defeat to Albania in their opening qualifier that saw Paulo Bento lose his job.
Fernando Santos' Portugal now sit second in Group I with two wins from three matches.
Despite the high-profile build-up to Tuesday's clash, Santos is in no mood to hype it up.
"[It] is a friendly," Santos is quoted as saying by Vavel.
"[It is] worth nothing. If it were a World Cup [it] would be special, but it counts for nothing."
Ronaldo is more excited and acknowledged: "It's always special to return to Old Trafford.
"[I] hope Portugal can win the game."
Ricardo Quaresma made another telling impact off the bench for Santos against Armenia and could be in line for a start.
It was no surprise to see Messi prove the difference against Croatia at Upton Park on Wednesday.
Croatia took a surprise lead before Cristian Ansaldi levelled proceedings - leaving Messi to hit the winning penalty in a 2-1 victory.
Gerardo Martino's side, still fine-tuning their preparations for next year's Copa America, have not played a competitive match since their heartbreaking World Cup final defeat to Germany in extra time.
That gives Portugal an edge - but Santos' men will have to contend with a forward line that could consist of any of Messi, Sergio Aguero, Gonzalo Higuain and the recalled Carlos Tevez.
Tevez did not start against Croatia, introduced as a 62nd-minute substitute, but may be involved from the beginning at Old Trafford - a ground he also formerly called home.
The two nations have played each other seven times before, but just once since 1972.
That clash came in February 2011, with Messi's 90th-minute penalty giving Argentina a 2-1 win - a match Ronaldo also scored in.