Introduction: Irisin and FGF-21 play an important role in the relationship between adipose tissue, skeletal muscle, and glucose homeostasis. Exercise modality can also be effective. This study aimed to compare the effect of different exercise training modes on serum irisin, FGF-21, and insulin resistance in overweight adolescent boys. Material and Methods: Fourty-eight eligible overweight adolescent boys were distributed in the following groups: control, high intensity interval training (HIIT), Moderate intensity Continuous Training (MICT), and Total Body Resistance Exercise (TRX). Different training modes were performed for 6 weeks. Before and after different types of exercise training, serum levels of irisin, FGF-21, and insulin resistance were measured. ANCOVA was used for statistical analyses. Results: BMI, weight, and body fat percentage, insulin, and glucose after training in the HIIT, MICT, and TRX groups were lower than in the control group. Despite the insulin resistance reduction and irisin promotion in response to different training, the levels of irisin and insulin resistance were not different between training groups (p>0.05), but FGF-21 in the MICT group was higher than in the TRX group (p≤0.05). Conclusion: In general, the results of this research showed that all three HIIT, MICT, and TRX training models led to a reduction in body fat, an increase in functional capacity, and glucose homeostasis amelioration to the same extent. The equal reduction in insulin resistance in response to various exercise modalities appears to occur through pathways independent of irisin, with the role of FGF‑21 being more pronounced in MICT.