Abstract: Hepatic encephalopathy (HE) is a severe clinical condition with limited therapeutic options. Silybin, a principal bioactive constituent of milk thistle, is a natural compound known for its protective effects against various liver diseases and neurodegenerative disorders. Silibinin meglumine (SM), the meglumine salt of silybin, is widely used in the management of hepatic disorders. However, the therapeutic potential and mechanistic basis of SM in HE remain incompletely elucidated. In this study, SM reduced serum ammonia levels and improved hepatic function markers, including alanine transaminase, aspartate transaminase, and total bilirubin (TBil), in thioacetamide (TAA)-induced HE mice. SM also attenuated inflammatory cytokines such as tumor necrosis factor (TNF) and interleukin-6 (IL-6) in both plasma and brain tissue, reduced the oxidative stress marker malondialdehyde, and increased glutathione levels. Furthermore, molecular docking, cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARTS) assay, and microscale thermophoresis (MST) assay collectively indicated that uncoupling protein 2 (UCP2) may serve as a direct molecular target of SM in mitigating HE. Notably, SM downregulated UCP2 expression in liver tissue and alleviated oxidative stress and mitochondrial dysfunction through modulation of the UCP2/PINK1/Drp1/mitofusin-2 (MFN2)/LC3B pathway. Additionally, co-administration of a UCP2 inhibitor partially attenuated the antioxidant effects of SM; however, no statistically significant reduction was observed in alanine aminotransferase (ALT) and aspartate aminotransferase (AST). In summary, this study demonstrates that SM-mediated targeting of UCP2 enhances hepatic mitochondrial function and suppresses excessive mitophagy, thereby ameliorating TBil in TAA-induced HE. These findings suggest that SM may represent a promising therapeutic strategy for TAA-induced HE.