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The former Argentina international, who won 75 caps for his country, was on the losing side as Miami were beaten 3-0 by reigning champions New York City FC.
Higuain had confirmed his plan to retire earlier this month and was in tears as he left the field, with a career that included spells with Real Madrid, Napoli and Juventus now at an end.
Gracias totales Gonza pic.twitter.com/XAKC6GWC43— Inter Miami CF (@InterMiamiCF) October 18, 2022
"I felt like what I had loved the most as a job had ended. It was half my life, my career, 17 and a half years," said Higuain, who previously spoke of plans to become a mental health coach, as he explained why he was moved to tears.
"Images from my entire career came to my mind – what I lived, what I worked, what I experienced – and I’m leaving very happy because I gave it all until today. That's the most important thing.
"The dream is over and another life begins."
A six-time domestic league champion – with three LaLiga crowns and three Serie A triumphs – the 34-year-old signed for the MLS club in September 2020.
He has left a lasting impression on the club and coach Phil Neville, having scored 29 goals in 67 MLS appearances.
"He's leaving in the way in which he should be leaving, with the goals he's scored, the happiness he's played with," said former Manchester United full-back Neville.
"The way he's embraced his team-mates and carried his team-mates is exactly what we expected. I think he can be massively proud.
"It's a massive adaptation period for any player to come to the MLS, particular when you've played in Europe, in the Champions League, to come here. I think it's a big learning curve if people come here and think it's going to be easy and it's not.
"I'm proud to have managed him. I think as a club we're proud to have had him. He leaves in a good moment, he helped us get to the Playoffs, and he can now enjoy his retirement. We wish him all the best, and he'll always be welcome."