Yes-associated protein (YAP) is a core effector molecule of the Hippo signaling pathway, which regulates transcription and controls cell proliferation and growth. However, the role of YAP in anti-tuberculosis drug-induced liver injury (ADLI) remains unclear. This study aims to investigate the regulatory effect of YAP on the NLRP3 inflammasome in ADLI and its potential ameliorative effects on liver injury. An ADLI animal model was established by gavage with a combination of isoniazid (INH), rifampicin (RFP), and pyrazinamide (PZA) in mice, and various indicators of experimental animals were detected at four time points: 0, 7, 14, and 21 days. On day 7, the successful establishment of the ADLI model in mice was confirmed by HE staining, supported by liver index and serum ALT and AST level tests. It was found that YAP inhibitors could slow the progression of ADLI, and there was no statistical difference between the model group and the model solvent group. Therefore, only the indicators of the 21-day control group, model group, and model inhibitor group were detected subsequently. The mRNA and protein levels of YAP were found to increase and then decrease due to the action of YAP inhibitors. Biochemical analysis showed that YAP could cause an increase in NLRP3 inflammasome indicators, leading to increased expression of inflammation and oxidative stress. After feeding with YAP inhibitors, these indicators decreased. The results of this study suggest that targeting YAP may be a novel therapeutic strategy to alleviate anti-tuberculosis drug-induced liver injury.