We here report the synthesis, structural characterization, and evaluation of the antiviral and antitubercular activities of a novel series of hybrid spirothiazolidinone derivatives (2a–f and 3a–f) containing the nicotinohydrazide moiety, which is an isomer form of the approved antitubercular drug isoniazid. When evaluated for activity against influenza A/H1N1, A/H3N2, and B viruses, three of the new compounds proved to possess specific antiviral activity against the influenza A/H3N2 virus. The most active analog 3a, bearing a 2,8‐dimethyl group at the spiro ring, displayed an antiviral EC50 value of 5.2 µM. Compound 3a produced no cytotoxicity at 100 µM, the highest concentration tested, giving a selectivity index of at least 19. Structure–activity relationship analysis indicated that the absence of the methyl substituent at the 2‐position and the presence of a bulky substituent at the 8‐position of the spirothiazolidinone system caused a significant decrease in antiviral activity. The in vitro antitubercular activity of compounds 2a–f and 3a–f was determined for six different drug‐sensitive/drug‐resistant laboratory strains and clinical isolates of Mycobacterium tuberculosis. Compounds 2c, 2d, 3b, 3c, and 3d showed weak antitubercular activity against different strains, with MIC values of 125–250 μM.