The World Cup winner came off the bench to bury a late free-kick, and snatch a win against Liga MX side Cruz Azul.
In the 92nd minute, the Argentine was fouled on the edge of the box, and stepped up to take a free-kick from 20 yards out. The result was a remarkable curler that kissed the top corner, and sent DRV PNK Stadium into raptures.
Inter Miami took a 1-0 lead in the contest, but conceded an equaliser shortly after Messi came on. Busquets was also handed his debut, while other new signing Jordi Alba is soon to follow.
Messi will feature again for Inter Miami as they take on Atlanta United in the Leagues Cup on Tuesday.