Messi scores off the bench as Inter Miami held by Colorado Rapids
The Argentine had been out of action for almost a month with a hamstring injury, missing the last four games, but was named among the substitutes for the home game.
Messi missed Wednesday's 2-1 home defeat to Mexico's Monterrey in the CONCACAF Champions Cup quarter-final and with the return game on Wednesday, Inter coach Gerard Martino rotated his squad.
Martino fielded a heavily second-string line-up with Messi's former Barcelona team-mates Luis Suarez, Sergio Busquets and Jordi Alba also on the bench.
The youthful line-up looked comfortable, without threatening too often, but fell behind on the stroke of half-time when defender Ryan Sailor lunged into a rash challenge in the box on Colorado's French forward Kevin Cabral.
The Rapids' Brazilian forward Rafael Navarro drilled home the penalty to give Colorado a 1-0 lead at the break.
Messi was brought on after the interval and made an instant impact.
After just 12 minutes on the field, the Argentine World Cup-winner brought Miami level when Franco Negri crossed low from the left and Messi fired home off the inside of the post.
Busquets was then introduced and Miami took the lead on the hour -- Messi bursting forward from midfield, feeding David Ruiz down the right and his cross was coolly converted by debutant Leonardo Afonso.
Messi then brought a fine save out of Colorado's former Manchester City goalkeeper Zack Steffen and then from a tight angle at the back post, struck the woodwork.
But the third goal never arrived and Miami paid the price in the 88th minute when Calvin Harris lead a counter-attack down the right and found Cole Bassett who slotted home the equaliser.