The current study aimed to investigate the effect of orally administered raspberry ketone (RK) on ameliorating nonalcoholic fatty liver disease (NAFLD) induced in rats by high-fat high-fructose diet (HFFD) in comparison to calorie restriction (CR) regimen. Thirty male Wistar rats were divided into two experimental groups; one was fed normal chow diet (NCD, n = 6) for 15 weeks to serve as normal control group and the other group was fed HFFD (n = 24) for 7 weeks to induce NAFLD. After induction, rats in the HFFD group were randomly allocated into four groups (n = 6 rats each). One group continued on HFFD feeding for 8 weeks (NAFLD control group). The remaining 3 groups received NCD, calorie-restricted diet, or NCD along with RK (55 mg/kg/day, orally) for 8 weeks. Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease with a global prevalence of 25.2% in the general population. The present work aimed mainly to evaluate the biochemical effects of Nigella sativa (NS) oil, raspberry ketone (RK) or dietary regimen on modulating metabolic changes in rat model of diet-induced fatty liver, focusing on adenosine monophosphate activated protein kinase (AMPK) pathway. This study provided evidence that NS oil or RK markedly ameliorate diet induced NAFLD in rats by activating the AMPK pathway, similar to calorie restriction.