Inspired by the medicinally relevant stilbene scaffold, a series of six electronically tuned benzylidene-based Schiff base derivatives were designed, synthesized, and characterized by FT-IR, ¹H NMR, ¹³C NMR, and ESI-MS analyses. The biological properties of the synthesized compounds were investigated through antioxidant, enzyme inhibitory, and antimicrobial assays, while molecular docking and density functional theory (DFT) calculations were performed to rationalize the experimental findings and structure-activity relationships. Compounds 3 and 6 exhibited the strongest antioxidant activities, particularly in ABTS, CUPRAC, FRAP, phosphomolybdenum, and metal-chelating assays. Compounds 1–3 and 5 demonstrated measurable α-glucosidase inhibitory activity, although they were less potent than acarbose, whereas compounds 1 and 2 showed the highest tyrosinase inhibition within the synthesized series. Antimicrobial evaluation revealed moderate activity across the series, with compound 3 displaying relatively higher antimicrobial activity within the synthesized series. Docking studies demonstrated favorable interactions within enzyme active sites, while DFT calculations provided insights into electronic properties and molecular reactivity. As a result, the investigated substitution patterns were associated with differences in biological activity within the synthesized series, with compound 3 showing relatively favorable activity in selected assays and warranting further investigation.