Tuberculosis is an ever-evolving infectious disease that urgently needs new drugs. In the search for new antituberculosis agents, a library of 3-cinnamoyl-4-hydroxy-6-methyl-2<i>H</i>-pyran-2-ones (CHPs) (<b>2a-2y</b>) was synthesized and evaluated against a standard virulent laboratory strain of <i>Mycobacterium tuberculosis</i> H37Rv. Out of 25 compounds, <b>11</b>, <b>5</b>, <b>7</b> and <b>2</b> (<b>2a</b> and <b>2u</b>) showed least, moderate, good and appreciable activities, respectively, based on minimum inhibitory concentrations (MICs). Both <b>2a</b> and <b>2u</b> exhibited an MIC value of 4 μg ml<sup>-1</sup>, which was close to those of standard antituberculosis drugs ethambutol, streptomycin and levofloxacin. Neither <b>2a</b> nor <b>2u</b> showed any activity against Gram-positive or Gram-negative bacteria and even against non-tuberculous mycobacterium, <i>i.e. Mycobacterium smegmatis</i>. Thus, like the antituberculosis drugs rifampicin, isoniazid and pretomanid, they are highly TB specific. All the pyrone-based chalcones showed no recognizable level of cytotoxicity against normal human kidney cell line (HEK-293) up to 80 μM concentration and 11 exhibited an IC<sub>50</sub> ≤ 100 μM (highest tested concentration). On further investigation, both <b>2a</b> and <b>2u</b> proved to be nontoxic against four human cell lines but <b>2a</b> proved to be a better choice as it did not reach IC<sub>50</sub> even at 100 μM (highest tested concentration) while the IC<sub>50</sub> of <b>2u</b> was around 80 μM. In conclusion, our results demonstrate that <b>2a</b> is specific against <i>M. tuberculosis</i> with no appreciable toxicity; its activity matches that of some clinically approved antituberculosis drugs and it therefore merits further evaluation.