Based on a previous report that α‐tetralone (3,4‐dihydro‐2H‐naphthalen‐1‐one) is a promising scaffold for the design of highly potent inhibitors of the enzyme, monoamine oxidase, the present study investigates the monoamine oxidase inhibitory properties of a synthetic series of fifteen C7‐substituted α‐tetralone derivatives. Arylalkyloxy substitution on C7 of the α‐tetralone moiety yielded compounds with high inhibition potencies toward the human monoamine oxidase‐B isoform with all compounds possessing IC50 values in the submicromolar range (0.00089–0.047 μm). The C7‐substituted α‐tetralones also were highly potent monoamine oxidase‐A inhibitors with thirteen (of fifteen) compounds possessing IC50 values in the submicromolar range (0.010–0.741 μm). The α‐tetralones were, however, in each instance selective for monoamine oxidase‐B over the monoamine oxidase‐A isoform. Dialyses of enzyme–inhibitor mixtures show that, while a representative inhibitor acts as a reversible monoamine oxidase‐A inhibitor, inhibition of monoamine oxidase‐B is not readily reversed by dialysis. Using a molecular modeling approach, possible binding orientations and interactions of selected α‐tetralones with the active sites of the monoamine oxidases are also proposed. This study suggests that C7‐substituted α‐tetralones are promising monoamine oxidase inhibitors and may represent lead compounds for the development of therapies for Parkinson's disease and depression.