Lycopene has known antioxidant, anti-inflammatory, anti-proliferative, and neuroprotective effects. This is the first study to evaluate the potential protective role of lycopene against hepatic encephalopathy. An experimental hepatic encephalopathy model was established by intraperitoneal administration of thioacetamide to rats. A total of 24 rats were randomized into four groups: healthy group, control group, low-dose (50 mg/kg) lycopene group, and high-dose (100 mg/kg) lycopene group. The locomotor activity test was measured on the first day of the study to determine baseline measurements and again at the end of the study to determine changes. Blood samples were collected, and liver, brain, and lungs were removed and weighed. Except for stereotypic movements (p>0.05), all other final locomotor activity tests were statistically significant (p<0.05). There was no statistical significance in IL-4 and IL-1RA analysis results (p>0.05), but IL-6, IL-10 and IL-1ꞵ analysis results were significant between control and healthy and high-dose lycopene groups (p<0.05). AST, ALT, total bilirubin, direct bilirubin and ammonia parameters were significantly lower in the low-dose lycopene group compared to the control and high-dose lycopene groups (p<0.05). Lycopene administration had hepatoprotective and neuroprotective efficacy against HE, supported both in locomotor activity tests and at biochemical tests.