Background: Nonalcoholic fatty liver disease (NAFLD) is characterized by oxidative stress and inflammation in the hepatocytes. Saffron and its constituents are reported to have several properties such as anti-inflammatory and anti-diabetic effects. Materials and methods: In a randomized double-blind placebo-controlled trial with two parallel groups including 76 eligible men and female patients with NAFLD aged 18-65, recruited from Hazrat Rasul Akram Hospital in Tehran, Iran. NAFLD was defined by a Gastroenterologist based on the American Gastrointestinal and Liver Association standards. Participants were randomly assigned to two groups receiving daily supplementation of either one tablet of 100 mg saffron (n = 38) or one placebo (n = 38) for 12 weeks. The primary outcome was high sensitive C-reactive protein (hs-CRP) and secondary outcomes were alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor alpha (TNF-α), malondialdehyde (MDA), total anti-oxidant capacity (TAC), leptin, adiponectin, anthropometric, and body composition Both groups were assigned similar diet and physical activity. Results: In the treatment group, significant decreases in hs-CRP (−1.80 ng/ml, 95% CI = −2.97, −0.63, p = .032), leptin (−0.27 ng/ml, 95% CI = −0.65, −0.10, p = .040), MDA (−1.01 ng/ml, 95% CI = −1.89, −0.14, p = .023) and significant increase in TAC (0.34 μmol/L, 95% CI = 0.08, 0.61, p = .011) were observed compared to the placebo group. However, there were no significant changes in serum alanine aminotransferase, AST, TNF-α, body composition, and anthropometric indexes (p > .05). Conclusion: In the present study, 12 weeks of 100 mg of saffron supplementation indicated beneficial effects on serum levels of some inflammatory, oxidative stress, and adipokines biomarkers but it had no significant effect on serum concentrations of liver enzymes, anthropometric, and body composition measurements.