AbstractFifteen 1,2,4-triazole derivatives were synthesised in this study and their MIC values againstMycobacterium tuberculosis(Mtb) ranged from 2 to 32 μg/mL. Furthermore, their antimycobacterial activity was positively correlated with the KatG enzyme docking score. Among the 15 compounds, compound4showed the strongest bactericidal activity with an MIC of 2 μg/mL. The selectivity index of compound4is more than 10, indicating that the compound has low toxicity to animal cells and has the potential to become a drug. Molecular docking indicates that compound4can bind firmly to theMtbKatG active site. The experimental results showed that compound4inhibitedMtbKatG and caused the accumulation of ROS inMtbcells. We speculate that compound4causes the accumulation of ROS by inhibiting KatG, and ROS produces oxidative destruction, leading to the death ofMtb. This study provides a new idea for the development of novel anti-Mtbdrugs.