Two new series of 2′-hydroxy-retro-chalcone derivatives have been synthesized and fully characterized by IR, 1H NMR, 13C NMR, and mass spectral data. All of these derivatives were evaluated for their antituberculosis activity against Mycobacterium tuberculosis H37Rv. Eight of the tested compounds inhibited the growth of the mycobacterial strain. Among them, compound (E)-1-[4-(decyloxy)phenyl]-3-(2-hydroxy-5-bromophenyl)prop-2-en-1-one was found to be the most active with MIC value of 27 μM. The results of this study suggest that chalcones are a class of compounds worthy of further investigation as an alternative inexpensive and synthetic therapeutic antituberculosis agent.