Messi cut a dejected figure after losing his fourth Copa America final, and fifth major final after Argentina’s loss to Germany at the 2014 World Cup, and said after the match he was retiring from the international game.
Argentina has now lost a fourth major final in nine years to defending champions, Chile.
Last year at the Copa America competition hosted by Chile, Argentina also lost at Chile at the final.
“It’s not meant for me. For me, the national team is over. I’ve done all I can, it hurts not to be a champion,” the 29-year-old said after defeat by Chile at the Copa America.
With Barcelona, Messi has won eight La Liga titles and four Champions Leagues. But his only major international honour is 2008 Olympic gold.
Argentina were beaten 1-0 in the 2014 World Cup final by Germany before two Copa America final defeats by Chile on penalties.
Messi was also on the losing side against Brazil in the 2007 Copa America final.
“It’s been four finals, I tried. It was the thing I wanted the most, but I couldn’t get it, so I think it’s over,” he said.
After Sunday’s match finished 0-0 in 120 minutes, Chile won 4-2 on penalties.
Messi’s miss was Argentina’s first attempt in the shootout and it ballooned over the bar after Sergio Romero had denied Chile’s Arturo Vidal.
Lucas Biglia also missed from 12 yards, with Chilean substitute Francisco Silva scoring the decisive spot-kick in the final in East Rutherford, New Jersey.
Messi had scored five times at the tournament, including a superb free-kick in the semi-final against hosts the USA to become his country’s record scorer with 55 goals.
For Barca, he has scored 453 times in 531 games, including a La Liga record 312 goals. He has won the Ballon d’Or award for the world’s best player five times.
Messi made his debut for Argentina in 2005, going on to make 113 appearances.
In 2014, he was named as the best player at the World Cup, with then-Fifa president Sepp Blatter saying he was “a little bit surprised” and Argentina legend Diego Maradona calling the decision “unfair”.
It started well for Argentina when their goalkeeper Sergio Romero got down to block Arturo Vidal’s opening penalty but Messi blasted over and Lucas Biglia’s spot kick was saved by Chilean goalkeeper Bravo Claudio.
Substitute Francisco Silva took Chile’s fifth penalty and struck it low and to the right of Romero to give his country their second successive title after winning their first on home soil last year.
“We’re going to enjoy ourselves,” Chile coach Juan Antonio Pizzi said, before talking of his pride in his players.
“Before them today was the number one team in the world, with the best players in the world and the best player in history.”
The tension of the penalty shootout barely made up for a disappointing game with few memorable moments for a sellout 82,000 crowd.
The bulk of first half action involved referee Heber Lopes, who sent off Chile’s Marcelo Diaz on 27 minutes for a second crude challenge on Messi, before Argentina’s Marcos Rojo was given a straight red for a rough tackle on Vidal about 15 minutes later.
Three others were booked, including Messi for diving, in a first half that had as many cards as shots on goal.
The second half provided more of the same and although Chile, who have never beaten Argentina in open play in 26 previous Copa America encounters, at least managed to call Romero into action, neither side created any clear cut chances.
The 30 minutes of extra time was not much different, although Vargas came close for Chile and substitute Sergio Aguero had a header tipped over by Bravo.
Five-times World Player of the Year Messi, who surpassed Gabriel Batistuta as Argentina’s top scorer in the semi-final against the United States, was heavily marked and had few chances to show his brilliance.
“It’s not easy to explain,” said Argentina coach Gerardo Martino.
“Argentina should have won that game. It hurts. There are situations we can explain football-wise and other situations that can be explained, if you will, talking about our luck.”
The tournament was played in the U.S. for the first time to commemorate the 100th anniversary of the inaugural competition and expanded to include six teams from North and Central America along with the 10 from South America.
Meanwhile, the Golden Ball, Glove and Boot awards of the tournament all went to Chile players following its penalty shootout win over Argentina in the Copa America final.
Arsenal’sAlexis Sanchez was crowned the Copa America Centenario’s Best Player after Chile won the tournament for the second successive year.
Sanchez received the Golden Ball award for his efforts throughout the centenary tournament in the United States, where he scored three goals and had four assists.
Chile captain and goalkeeper Claudio Bravo took out the Golden Glove for a second consecutive year after playing a starring role in the decider.
Bravo produced a stunning save to thwart Sergio Aguero in the second half of extra time and the Barcelona keeper denied Lucas Biglia from the spot to allow Francisco Silva to convert the winning penalty.
The 33-year-old shot-stopper – Chile’s most capped player with 106 – kept three clean sheets in this year’s edition of the Copa America.
Chile forward Eduardo Vargas won the Golden Boot, having topped the goal-scoring chart with six.
Vargas, who finished level with Paolo Guerrero last year, stamped his mark on the tournament with a four-goal haul in Chile’s 7-0 demolition of Mexico in the quarter-finals.