The discovery of new chemical entities endowed with potent, selective, and reversible monoamine oxidase B inhibitory activity is a clinically relevant subject. Therefore, a small library of chromone derivatives was synthesized and screened toward human monoamine oxidase isoforms (hMAO-A and hMAO-B). The structure–activity relationships studies strengthen the importance of the amide spacer and the direct linkage of carbonyl group to the γ-pyrone ring, along with the presence of meta and para substituents in the exocyclic ring. The most potent MAO-B inhibitors were N-(3′-chlorophenyl)-4-oxo-4H-chromene-3-carboxamide (20) (IC50 = 403 pM) and N-(3′,4′-dimethylphenyl)-4-oxo-4H-chromene-3-carboxamide (27) (IC50 = 669 pM), acting as competitive and noncompetitive reversible inhibitors, respectively. Computational docking studies provided insights into enzyme–inhibitor interactions and a rationale for the observed selectivity and potency. Compound 27 stands out due to its favorable toxicological profile and physicochemical properties, which pointed toward blood–brain barrier permeability, thus being a valid candidate for subsequent animal studies.