The Albiceleste faced a crunch game in La Paz, which had already been made difficult enough by the altitude, but they also had to contend with the absence of their best player.
Without Messi to call upon, Edgardo Bauza's side struggled for inspiration and saw goals from Juan Carlos Arce and Marcelo Moreno consign them to their fourth defeat of the qualification campaign.
The result leaves Argentina's hopes of reaching next year's World Cup in jeopardy, with the race for qualification tightening. The three-time world champions have four games remaining and Messi will miss three of them, against Uruguay, Paraguay and Venezuela.
Messi has been retrospectively punished for insults aimed at – and comments about the mother of - Brazilian assistant referee Emerson de Carvalho during Argentina’s 1-0 win over Chile last week.
The Barcelona forward was caught on video invoking “the c*** of [Carvalho’s] mother” as he raged against an officiating decision. Match referee Sandro Ricci did not include the incident in his report but Fifa confirmed they were investigating regardless after being made aware of the footage.
Messi would later refuse to shake the official’s hand and Ricci denied hearing anything.
“I didn't hear any offensive language from Lionel Messi or anyone else towards myself,” he said. “If I heard any offensive words, I would have acted according to the rules of the game.”
Messi will now not feature in Argentina's qualification efforts until their final fixture against Ecuador.
Bolivia has been a historically difficult place to go for visiting teams, with the Estadio Hernando Siles the highest football ground in the world. It even falls outside the rules set by Fifa, but was handed special exemption to host international fixtures.
Diego Maradona’s Argentina were famously thrashed 6-1 in La Paz as they wobbled en route to World Cup 2010 while Messi and Angel Di Maria both needed oxygen masks during qualification for the 2014 tournament.