OBJECTIVES: To investigate the therapeutic role of calorie-restricted diet (CR) and raspberry ketone (RK) in non-alcoholic fatty liver disease (NAFLD) and the implication of sphingosine kinase-1 (SphK1)/sphingosine-1-phosphate (S1P) and toll-like receptor 4 (TLR4) signalling. METHODS: NAFLD was induced by feeding rats high-fat-fructose-diet (HFFD) for 6 weeks. Rats were then randomly assigned to three groups (n = 6 each); NAFLD group continued on HFFD for another 8 weeks. CR group was switched to CR diet (25% calorie restriction) for 8 weeks and RK group was switched to normal diet and received RK (55 mg/kg/day; orally) for 8 weeks. Another six rats were used as normal control. KEY FINDINGS: HFFD induced a state of NAFLD indicated by increased fat deposition in liver tissue along with dyslipidemia, elevated liver enzymes, oxidative stress and inflammation. Either CR diet or RK reversed these changes and decreased HFFD-induced elevation of hepatic SphK1, S1P, S1PR1 and TLR4. Of notice, RK along with a normal calorie diet was even better than CR alone in most studied parameters. CONCLUSIONS: SphK1/S1P and TLR4 are interconnected and related to the establishment of HFFD-induced NAFLD and can be modulated by RK. Supplementation of RK without calorie restriction to patients with NAFLD unable to follow CR diet to achieve their treatment goals would be a promising therapeutic modality.