A series of substitututed methylene/ethylene 4-fluorophenylhydrazide derivatives (3a–p) was synthesized with the aim of evaluating their antimycobacterial activity toward a strain of Mycobacterium tuberculosis H37Rv. Their chemical structures were confirmed by 1H-nuclear magnetic resonance (NMR) and electrospray mass spectrometry (ES-MS) spectral data, and elemental analysis. The in vitro antimycobacterial evaluation was performed according to the Tuberculosis Antimicrobial Acquisition and Coordinating Facility (TAACF) antituberculosis drug discovery program. Compound 3a, 4-fluorobenzoic acid [(2,6-dichlorophenyl) methylene]hydrazide, showed the highest inhibitory activity of all the compounds under study.