Nonalcoholic fatty liver disease (NAFLD) is a complex hepato-metabolic syndrome with multi-etiological pathways. No effective drugs have been settled for the effective therapy of NAFLD. The purpose of this study was to investigate the modulatory effects of cilostazol (CILO, 50 and 100 mg/kg.p.o.) against NAFLD induced by high fat diet rich in cholesterol (HFD-CH) for 10 weeks. Thirty male Sprague dawely rats were divided into 4 groups (8 rat / group).Normal control group supplied with normal chow diet. Control positive group received high fat diet rich in cholesterol for 10 weeks. In addition, two CILO groups received (CILO, 50 and 100 mg/kg.p.o.). Oral administration of (CILO; 100 mg/kg) showed promising results in reducing fasting glucose and insulin levels. Moreover, CILO could reduce the elevated hepatic lipids, oxidative stress biomarkers and inflammatory cytokines. In addition, CILO succeeded to restore the total protein levels and activate nuclear factor erythroid-related factor 2/ heme oxygenase-1 (Nrf2/HO-1) activity. Furthermore, administration of CILO for NAFLD rats succeeded to show corrected and normalized FTIR spectra. We also investigated the plausible binding interactions of CILO with various biological targets using a molecular docking approach, and the results showed that CILO had an excellent docking energy score and significant binding interactions with the core amino acids involved in the active pocket for the enzymes studied. This study depicts that CILO exerted new intervention for NAFLD due to its complementary antihyperlipdemic, anti-inflammatory effects and antioxidant potential, via Nrf2/HO-1 activation.