The Argentine scored in the second half but Miami's defence was once again exposed as they fell to a fourth defeat in their last five games in all competitions -- a run which has seen them concede 14 goals.
Miami had lost their last three games, including a 5-1 aggregate defeat to the Vancouver Whitecaps in the Champions Cup semi-finals, but they got a much-needed morale boost with a comfortable Major League Soccer victory.
A dejected-looking Lionel Messi walked off the field in defeat on Wednesday after his Inter Miami team were exposed in emphatic fashion by a young Vancouver Whitecaps.
For Messi's Miami, the focus will turn to their bid for a first MLS Cup and their FIFA Club World Cup campaign.
Messi's impact was limited -- he was quickly closed down by Vancouver and was restricted to an optimistic long-range effort in the 29th minute which flew high over the bar.
A crowd of 60,614 turned out at Huntington Bank Field, the home of the NFL's Cleveland Browns, for the visit of Lionel Messi and friends and while the Argentine had a quiet game, Miami left with the points.
“No, yes in a joking tone we often talk, but he has those desires to play the World Cup next year too,” Suarez told Ovacion.
A club-record crowd of 62,358 packed into Soldier Field for the visit of Lionel Messi and his Inter team to witness a gutsy display from the home side.
Messi tucked the 84th minute spot kick into the corner to complete the comeback for Miami and earn them a place in the last four.
The eight-times Ballon d'Or winner hadn't played since injuring his right ankle during the Copa America final on July 14, when he helped Argentina to victory over Colombia.
Lionel Messi is set to return to action with his club Inter Miami on Saturday after spending over two months out with an ankle injury, Miami coach Gerardo Martino said on Friday.
Miami, once again without Lionel Messi, who continues to be sidelined by an ankle injury, have already secured their place in the playoffs and remain in top place for the regular season 'Supporters' Shield'.
"There were specific drills that we devised that would allow him a certain level of participation," coach Tata Martino told the outlet. "But he still does not have medical clearance (to play)."
Luis Suarez struck twice as ten-man Inter Miami became the first team to book their place in this season's Major League Soccer playoffs after beating Cincinnati 2-0 at Chase Stadium on Saturday.
Messi, 37, has been away from the team since he suffered a high-ankle injury on July 14 playing for Argentina against Colombia in the Copa America final.
Diego Rossi's two second-half goals launched the reigning MLS champion Columbus Crew over defending champion Inter Miami 3-2 to reach the Leagues Cup quarter-finals on Tuesday.
Argentine star Lionel Messi was ruled out on Monday by Inter Miami coach Gerardo Martino for the defending champions' Leagues Cup knockout match on Tuesday at reigning MLS champion Columbus.
Messi suffered a right ankle ligament injury in last month's Copa America final, helping Argentina to victory over Colombia, but Martino said the 37-year-old Argentine striker is getting better.
Paraguay's Matias Rojas opened the scoring in the ninth minute and Uruguayan striker Luis Suarez added an insurance goal in the 72nd minute to deliver Inter Miami's triumph.