Diego de Souza scored in the 27th minute to give Defensor a 3-2 aggregate win in the second round tie and hand Boca their first home defeat in the competition since 2003, a run of 30 matches.
Defensor will face Estudiantes, Argentina's sole survivors in the competition, in the quarter-finals.
Boca had an early chance when Fabian Vargas headed wide from Rodrigo Palacio's cross but, with playmaker Juan Roman Riquelme drifting in and out of the game, Argentina's most popular team failed to take control.
The Uruguayan championship leaders went ahead when De Souza was first to Pablo Pintos' cross and scored with a shot on the turn which went in off the underside of the crossbar.
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