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. It is associated with several comorbidities, either hepatic as steatohepatitis, fibrosis, cirrhosis and even hepatocellular carcinoma or non-hepatic complications such as cardiovascular diseases, chronic kidney disease, diabetes mellitus and polycystic ovarian syndrome. 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 NAFLD, focusing on adenosine monophosphate activated protein kinase (AMPK) pathway. Overall, NAFLD is associated with metabolic adverse effects via impairment of the AMPK signaling pathway, leading to dyslipidemia and hepatocellular injury. 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 (CR). These natural products can be used with normal diet to provide additional benefit over CR treatment by overcoming the poor compliance to long term CR regimen.