Background: Insulin resistance can be a predictor of adverse fatty liver disease and health problems. Objectives: The present study aimed to investigate the effect of insulin resistance on fatty liver disease. Methods: This study used the data of 2,160 individuals registered in a cross-sectional study who were randomly selected from among clients of a nutrition clinic in Tehran from April to December 2019. Insulin resistance and beta-cell activity were calculated by the homeostasis model assessment formula. The study outcome was defined as having fatty liver disease. The odds ratio (95% CI) was calculated using logistic regression models. Results: The mean age was 35 (± 9) in healthy subjects and 49 (± 8) in fatty liver disease patients (age range: 16 to 42 years). Nearly 34.5% of the individuals had fatty liver disease. According to the adjusted results of the logistic regression model, the risk of NAFLD was 1.05 (P < 0.001) for one unit increase in fasting insulin and 1.01 (P < 0.001) for one unit increase in 2-h insulin, which indicated the statistically significant relationship of NAFLD with fasting insulin and 2-h insulin. Also, the risk of NAFLD was 1.01 P < 0.001) for one unit increase in FPG, which was statistically significant. Moreover, the adjusted risk of NAFLD was 1.00 (P < 0.001) for one unit increase in 2-h glucose, which was not statistically significant. Finally, the adjusted risk of NAFLD was 1.29 (P < 0.001) for one unit increase in HOMA-IR, which was statistically significant. Conclusions: The findings of the present study demonstrated that insulin resistance could increase the risk of fatty liver disease. Also, each one-unit increase in fasting blood sugar, fasting insulin, and 2-h insulin increased the risk of fatty liver disease. Therefore, the results of this study may be useful for health policymakers to design suitable preventive and therapeutic interventions for those with NAFLD to prevent and control this disease.