Background and Aim: Non-alcoholic fatty liver disease (NAFLD) is characterized by the accumulation of excess fat in the liver, causing liver cell damage, increased inflammation, and weight gain. Despite its high prevalence, diagnosis and follow-up of the disease is difficult. Irisin, a slimming myokine produced in response to physical activity (PA), exhibits anti-inflammatory and anti-obesity effects. This study aimed to investigate changes in irisin levels, inflammation markers (tumor necrosis factor-α [TNF-α] and interleukin-6 [IL-6]), and myeloid differentiation factor-2 (MD2) levels in NAFLD, as well as anthropometric and routine biochemical parameters, by providing PA recommendations and nutrition education (NE) to individuals diagnosed with NAFLD over a period of 12 weeks., Methods: The study included 62 patients diagnosed with NAFLD who did not use alcohol. They were divided into groups: PA, NE, both (NE + PA), and untreated (control) patients. Patients receiving NE were provided with 1-h NE sessions every 4 weeks for 12 weeks, and their personal information, nutritional status, 24-h retrospective food consumption record, and anthropometric measurements were recorded at the beginning (day 0) and end (week 12) of the study. The PA group was recommended aerobic walking for 30 min, 5 days a week. At the beginning (day 0) and end (week 12) of the study, patients' anthropometric and routine biochemical tests were conducted, and irisin, MD2, TNF-α, and IL-6 levels were measured using the ELISA method., Results: All groups were similar in demographic characteristics and dietary habits. After 12 weeks, there were no significant differences in biochemical parameters among the groups. Glucose levels increased in the untreated group but decreased in the PA and PA + NE groups compared to baseline, with a significant decrease in the PA group. Insulin levels significantly decreased in the NE group. The PA + NE group showed decreased aspartate aminotransferase (AST), gamma-glutamyl transferase, alkaline phosphatase, total cholesterol, low-density lipoprotein, and triglyceride levels and significant decrease in ALT levels. AST decreased significantly in the PA group while high-density lipoprotein increased significantly. There were no statistically significant differences between the groups in irisin, MD2, IL-6, and TNF-α levels. After 12 weeks, irisin levels significantly increased in nutrition and PA groups except the untreated group. There were no statistically significant differences in IL-6 and MD2 levels compared with baseline after 12 weeks. PA recommendations alone were not effective in observing significant changes in anthropometric measurements in individuals with NAFLD. It was detected that only nutritional recommendations provided a significant decrease in body fat ratio but were insufficient for the change in other anthropometric measurements. In the group where NE and PA were recommended together, a significant decrease in anthropometric measurements was found. The NE group significantly reduced their energy and carbohydrates (%EI) intake after 12 weeks of intervention compared with the baseline., Conclusion: NE and PA recommendations led to improvements in liver-related biochemical parameters and significant reductions in anthropometric measurements among individuals with NAFLD. Moreover, patients receiving NE experienced a decrease in energy and carbohydrates intake as a percentage of total energy intake (%EI). Increased irisin levels in NE, PA, and NE + PA groups may have contributed to the decrease in body fat percentage., (© 2024 The Author(s). Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)