Asymmetric catalytic cascade processes are powerful since they offer direct access to complex chiral molecules from simple substrates and in a single step. In biocatalysis, cascades are generally designed by combining multiple enzymes, each catalyzing individual steps of a reaction sequence. Herein, we report a different strategy for biocatalytic cascades based on a single multifunctional enzyme that can promote multiple stereoselective steps of a domino process by mastering distinct catalytic mechanisms of substrate activation in a sequential way. Specifically, we have used an engineered 4-oxalocrotonate tautomerase (4-OT) enzyme with the ability to form both enamine and iminium ion intermediates and combine these mechanisms of catalysis in a complex sequence. This approach allowed us to activate aldehydes and enals toward the synthesis of enantiopure cyclohexene carbaldehydes bearing multiple stereogenic centers. The multifunctional 4-OT enzymes could successfully promote both a two-component reaction and a triple cascade characterized by different mechanistic features and activation sequences. This study demonstrates that biocatalytic strategies can match and even surpass in efficiency the potential of organocatalytic cascade catalysis.