Messi endured an injury-hit start to 2019-2020, but has shown little sign of rustiness since returning to full fitness, and followed up his record sixth Ballon d'Or win with a hat-trick in Barca's 5-2 win over Real Mallorca on Sunday (AEDT).
However, with Barca's place in the last 16 already secured thanks to a 3-1 victory over Borussia Dortmund in its previous Group F fixture, it appears Ernesto Valverde has decided to rest Messi for the trip to Milan.
After Tuesday's match at San Siro, Barca faces Real Sociedad before taking on Real Madrid in the rearranged Clasico on 19 December, with another league match against Deportivo Alaves capping off 2019 three days later.
Messi is not the only star name to be left out of Barca's squad, with Gerard Pique also missing, while Jordi Alba and Nelson Semedo continue their respective recoveries from hamstring and calf problems. Arthur and Ousmane Dembele are absent through injury as well.
Luis Suarez, who scored both goals in Barca's 2-1 win over Inter in October, is included within the 20-man squad, as is Antoine Griezmann.
While Barca's place in the knockouts is secured, Inter need to at least match Dortmund's result against Slavia Prague if they are to guarantee progression.