Nonalcoholic fatty liver disease (NAFLD) is a multi-etiological hepato-metabolic syndrome. No effective drugs have been settled for the effective therapy of NAFLD. Our study was conducted to evaluate 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. Forty male Sprague dawely rats were divided into 4 groups (10 rat / group). Normal control group supplied with normal chow diet. Control positive group received HFD- CH for 10 weeks. In addition, two CILO groups received (CILO, 50 and 100 mg/kg.p.o.) concurrently with HFD- CH. Our findings revealed that CILO at a dose level (100 mg/kg) showed promising results in reducing fasting glucose and insulin levels. Moreover, it could reduce the elevated inflammatory cytokines, hepatic lipids, and oxidative stress biomarkers. In addition, CILO succeeded to restore the total protein levels and activate nuclear factor erythroid-related factor2/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 confirmed that CILO exerted a new intervention for NAFLD due to its complementary anti-hyperlipidemic, anti-inflammatory, and antioxidant potential, which was achieved through Nrf2/HO-1 activation.