The powder of a crude extract from earthworms was used as a catalyst in three-component cascade Mannich-Michael reaction for the preparation of isoquinuclidine (azabicyclo[2.2.2]octane) derivatives. The influences of mole ratio of substrates, solvents, water contents, catalyst loading, temperature, and reaction time on the reaction were investigated. The developed system had excellent substrate adaptability. Various isoquinuclidines were obtained in yields of up to 99% with ratio of endo/exo of up to 76:24. This method provided a good example to use naturally existing catalyst for organic synthesis.