With their place in the quarter-finals already certain, Albirroja coach Eduardo Berizzo rotated his squad for this final group match but still named Almirón - who has been one of the tournament's outstanding players - in the starting XI in Rio de Janeiro.
But half an hour into the game, the Newcastle United man suffered an apparent hamstring injury, pulling up as he attempted to accelerate, and was visibly devastated as he left the field to be replaced by Óscar Romero in the 33rd minute.
Paraguay were behind to a 21st-minute Edinson Cavani penalty and there were no further goals as Almirón watched on from the bench.
But they were already guaranteed to finish at least third in Group A and will now take on Peru at Estádio Olímpico Pedro Ludovico in Goiânia in the last eight on Friday - although it seems unlikely that Almirón will be able to play.