A series of benzylsulfanyl benzo-heterocycle amides and hydrazones were synthesized and evaluated for anti-tubercular activities. The isonicotinyl hydrazone derivatives 12d, 12e and 12f exhibited good anti-tubercular activity against Mycobacterium tuberculosis H37Rv (ATCC #27294) with MIC values of 0.23, 0.24 and 0.24 μM, respectively, and were also active against SDR-TB, MDR-TB and XDR-TB. More importantly, compound 12e also showed low cytotoxicity and good metabolic stability, and could significantly reduce the mycobacterial burden in a mouse model infected with autoluminescent H37Ra strain, which may serve as a lead compound for further development.