Curcumin is a natural product that has been reported to exhibit myriad pharmacological properties, one of which is antitubercular activity. It demonstrates antitubercular activity by directly inhibiting Mycobacterium tuberculosis (M.tb) and also enhances immune responses that ultimately lead to the elimination of M.tb by macrophages. This natural product is, however, unstable, and several analogues, noticeably monocarbonyl analogues, have been synthesized to overcome this challenge. Curcumin and its monocarbonyl analogues reported so far exhibit moderate antitubercular activity in the range of 7 to 16 μM. Herein, we report a straightforward synthesis of novel monocarbonyl curcumin analogues, their antitubercular activity, and the structure-activity relationship. The hit compound from this study, 3a, exhibits potent MIC 90 values in the range of 0.2 to 0.9 μM in both ADC and CAS media.