Topiramate (TPM), a carbonic anhydrase (CA) inhibitor, is known for its anti-obesity effect. Even though, nonalcoholic fatty liver disease (NAFLD) is present in 80% of obese patients, TPM’s effects on oxidant-antioxidant parameters and CA activity on fatty liver is not known. 24 Wistar albino rats were divided into four groups: control, TPM, diet, and diet + TPM. Diet groups fed with high-fat diet while control and TPM groups received standard chow for six weeks. Than 100 mg/kg/day TPM (po) was added to TPM groups for 21 days. Rats’ weight and blood glucose levels were monitored weekly, and at the end of the study liver removed for biochemical and histological analysis. TPM eliminated the increases in weight and blood glucose levels caused by high-fat diet. TPM decreased CA activity in all groups. MDA levels increased significantly in TPM and DT groups (p = 0.004; p = 0.008). GSH levels were decreased in the TPM, D and DT groups (p = 0.004; p = 0.015; p = 0.003). Similarly, GPx activity levels were significantly decreased in all groups. Histological evaluation revealed notable infiltration, eosinophilia and cytoplasmic vacuolization in the TPM group. Steatosis and NAFLD activity score (NAS) were higher in the diet group. Ballooning, infiltration and NAS were higher in the diet + TPM group compared to control. CA activity negatively correlated with MDA (p < 0.001), and positively correlated with GSH (p < 0.001). TPM caused oxidant stress and liver damage, which are exacerbated in NAFLD induced rats. Therefore, use of TPM in patients with liver disease should be considered very carefully.