The present study describes the synthesis of a novel series of 1,3,4-thiadiazole-based Schiff base derivatives (6a–f) and their evaluation for antimicrobial, antioxidant, and antitubercular activities. The target compounds were synthesized through a two-step protocol. Initially, thiosemicarbazide was cyclized with substituted aromatic acids in ethanol to afford the corresponding 5-phenyl-1,3,4-thiadiazol-2-amine intermediate. Subsequently, condensation of this intermediate with various heterocyclic aldehydes in ethanolic medium using acetic acid as a catalyst furnished the desired Schiff base derivatives (6a–f). The structures of the synthesized compounds were established by FT-IR, 1H NMR, 13C NMR, mass spectrometry, and elemental analysis. The synthesized derivatives were subsequently screened for their antioxidant, antimicrobial, and antitubercular activities. Among the investigated compounds, derivative 6a exhibited the most promising activity across all three biological assays, highlighting its potential as a lead scaffold for further structural optimization and biological investigation.