Indole-3-carbinol (I3C) is reported to have hepatic and neuroprotective properties. However, the I3C role in the protection of the liver and brain in the pathological condition of hepatic encephalopathy has not been investigated. Therefore, in the present study, we have assessed the hepatic and neuroprotective roles of I3C against thioacetamide (TAA)- induced hepatic encephalopathy in Wistar rats. TAA (300 mg/kg) was intraperitoneally administered to Wistar rats to induce hepatic encephalopathy. The elevated levels of ammonia in the blood, liver, and brain were substantially lowered by I3C treatment (25, 50, and 100 mg/kg, oral, 7 days). I3C significantly ameliorated the TAA-induced liver dysfunction by decreasing the alanine transaminase, aspartate transaminase, and alkaline phosphatase enzymes and reduced the elevated cytochrome P4502E1 (CYP2E1) activity in the liver and brain. Further, I3C alleviated mitochondrial dysfunction and oxidative stress in the brain. I3C treatment improved the anti-inflammatory cytokine interleukin (IL)- 10 while reducing inflammatory cytokines such as tumor necrosis factor-1 and IL-6 in hepatic encephalopathy rats. I3C reduced the levels of apoptotic indicators mediated by the mitochondria, including cytochrome c, caspase 9, and caspase 3. Concurrently, I3C mitigated the liver and brain histological abnormalities in hepatic encephalopathy rats. Therefore, the present study concluded that the I3C protected the liver and brain from TAA-induced hepatic encephalopathy injury by inhibiting CYP2E1 enzyme activity and decreasing ammonia, oxidative stress, inflammation, and apoptosis. The present study provides preclinical validation of I3C use as hepatic and neuroprotective for hepatic encephalopathy management.