Barcelona captain Messi missed his team's 2-0 defeat of Inter two weeks ago, with Rafinha deputising and scoring against his old club in the Group B meeting.
"It is a pleasure to see Messi play but I hope he can hold a little more on the bench," Zanetti said to Marca. "Knowing for sure he has a crazy desire to play.
"I expect a very complicated game, they have quality in all their lines but Inter have all the conditions to be able to beat them. We both arrived at a good time.
"I do not think we will see a very different Barca, but they will go out and do the same, they never change their philosophy. They will want to have the leading role but we will be able to counteract that."
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Messi has not played for Argentina since their disastrous World Cup campaign, which saw Jorge Sampaoli sacked following his side's last-16 exit against winners France.
The captain, beaten in the 2014 World Cup final and two Copa America finals, has yet to confirm when he may return to international action and is not in the squad for an upcoming double-header of friendlies against Mexico.
"Argentina have good players constantly but to make things go well, there is still a lot to work," added Zanetti, who won 143 caps for the Albiceleste.
"The pressure that has suffered the last generation of Argentine footballers has been for the three lost finals, we are a successful country but you can not measure a group just for that, but for how it reached those finals.
"Leo is so big that we have to enjoy him much more. We Argentines do not realise what Leo represents for the whole world."
Inter welcome Barca to San Siro having won their last seven Serie A matches, but despite strong progress under Luciano Spalletti, Zanetti feels there is more work needed at the club.
"This is a club where there is a lot to do. We are in a very solid, positive moment, especially since the Chinese investment," Zanetti said. "There is still much room for improvement in everything.
"Inter came from a stage of difficulties but with the arrival of Suning, everything was restructured. What I have clear is that in order for things to work on the pitch, they must also do so off it.
"For that, we have surrounded ourselves with people who know the DNA of Inter. I work on the key projects in the brand evaluation, social impact and international relations that have helped the club a lot.
"Qualifying for the Champions League last year was the starting point. For us it is key to have continuity in it, to be always in this constitution but beyond good results, we must be a sustainable club and grow in all areas."