The precise mechanism of caffeine modulating effects on NAFLD is completely unknown. So, the aim of this study was to evaluate the modulating effects of caffeine on some biochemical markers in obesity induced NAFLD. Forty male albino rats were divided into four groups of 10 rats each. The rats of group 1 served as normal control. Group 2 received control diet and caffeine in a concentration of 1g/L orally. Group 3 received a high fat diet (HFD). Group 4 received high fat diet and was given caffeine just like group 2. After 20 weeks, serum and liver tissues were obtained from the sacrificed rats. Total lipid profile, blood glucose levels, liver triacylglycerols (TAGs) and serum activity of alanine aminotransferase (ALT) were estimated. Tissue 4-hydroxy-2-nonenal (4-HNE) as a marker for oxidative stress, calgranulin S100 A8, receptor for advanced glycation end products (RAGE) and toll like receptor-4 (TLR4) were immunoassayed. Plasma caffeine levels were estimated by ultra performance liquid chromatography. NAFLD was confirmed by histopathological results as well as increased serum activity of ALT, marked dyslipidemia and high blood glucose levels. NAFLD led to elevations in liver TAGs, 4 –HNE, calgranulin S100 A8, RAGE and TLR4. Improvement in all assessed parameters except TLR4, was observed in NAFLD rat group treated with caffeine. Caffeine had a modulatory action on NAFLD which may be through improving the antioxidant status in hepatic tissue and/or suppressing some inflammatory cascades. It is hoped that these findings would assist in development of NAFLD management strategies that may use caffeine as a potential drug for treatment.