The 38-year-old Argentine icon confounded the Timbers' defence all night long in a timely reminder of the danger he still poses at the World Cup, which kicks off in less than a month.
Messi struck first, starting and finishing a slick team goal for the defending Major League Soccer champions on the half-hour mark.
Messi laid off the ball to Luis Suarez, who found Telasco Segovia with a through ball. Segovia's instinctive backheel landed back at the feet of Messi, who swept it into the far corner from close range.
Ten minutes later, fellow Argentine Rodrigo De Paul romped up the right flank, finding Messi who played a one-two with Suarez.
The eight-time Ballon d'Or-winner then slalomed his way into the box, through four defenders, before using the outside of his left foot to tee up German Berterame for a tap-in.
Messi missed chances to add to his tally in a slower and goalless second half, curling a left-foot strike from outside the box just inches wide of the post.
And he nearly added a stunning free kick deep into stoppage time, denied by a superb James Pantemis save, who dove at full stretch and barely tipped the ball away from the top corner.
It was the fifth home game at the gleaming, purpose-built Nu Stadium, which was opened to great fanfare last month.
Until now, the 27,000-capacity arena had witnessed three frustrating draws and a humiliating Miami collapse from 3-0 up to lose 4-3 to Orlando City.
Despite their recent struggles at home, the win sends Inter Miami top of the Eastern Conference, one point clear of Nashville SC, who have two games in hand.
The World Cup, being held in the United States, Mexico and Canada, kicks off June 11.
Along with Cristiano Ronaldo, Messi - who lifted the trophy with Argentina at the last edition, in Qatar - is set to become the first player to appear in six different World Cups.
