The ketogenic diet (KD) is a dietary plan enriched in fat and lower in carbohydrates designed to treat obesity through boost the production and consumption of ketone bodies. The aim of this study was to explore the hepatic effects of ketogenic diet during treatment of obesity in HFD-rats and to compare these effects with orlistat and β-hydroxybutyrate (BOHB). The rats were assigned into two essential groups: Group I, healthy control group, and Group II: obese rats subdivided into 5 groups: group IIA: untreated obese rats, Group IIB: treated orally with orlistat, Group IIC: treated orally with BOHB, Group IID: treated orally with combination of BOHB and orlistat and Group IIE: feed with KD. After two months of treatments, rats were sacrificed and blood samples and hepatic tissues were obtained for assessments of serum biochemical parameters and BOHB, and hepatic phosphatidylinositol 3-kinases (PI3k), protein kinase B (AKT), mammalian target of rapamycin complex 1 (mTORC1), and sterol regulatory element binding proteins 1c (SREBP-1c) expression at mRNA and protein levels. Only the KD significantly declined the weight gain while all treatments significantly corrected hyperglycemia, elevated insulin levels, and insulin resistance. KD reversed the dysregulated hepatic expression of PI3K, AKT, mTORC1, and SREBP-1c at both mRNA and protein levels. Also, BOHB alone or combined with orlistat resulted in a considerable improvement of the altered genes. The current study's findings provide evidences for the anti-obesity potential of KD and BOHB through the amelioration of glucose and lipid homeostasis, insulin sensitivity and hepatic PI3K /AKT/mTOR pathway.