Ecuador qualified for the 2022 World Cup on Thursday despite a 3-1 defeat to Paraguay, benefiting from a victory for Uruguay that also sent the two-time champions to Qatar.
La Tri, who failed to make Russia 2018, knew they needed only a point to be sure of a top-four finish with a game to spare.
However, already-eliminated Paraguay were clinical in Ciudad del Este, three up before the hour mark through Robert Morales, a Piero Hincapie own goal and Miguel Almiron.
Ecuador threatened a dramatic fightback as Jordy Caicedo scored a late penalty and Blas Riveros was sent off, but ultimately their fate was decided in Montevideo.
The third-placed side joined Uruguay in advancing with both teams on 25 points, four ahead of fifth-placed Peru, who went down 1-0 to Giorgian De Arrascaeta's goal late in the first half.
Peru are still in control of their play-off fate, although both Colombia and Chile can catch them as Paraguay attempt to again play the role of spoilers in Tuesday's final match in Lima.