Abstract Background To investigate changes in levels of myokines after regular aerobic training and resistance training in post- menopausal females with obesity. Methods A community-based a randomized controlled trial study was 41 post- menopausal females with obesity from Buk-gu community center, Chuncheon, Gangwon-do, Republic of Korea, from November 2017 until the end of October 2018. Among 41 post- menopausal obese females volunteered to participate in this study performed regular physical exercise training (aerobic exercise and resistance exercise). These participants were randomly assigned to one aerobic exercise group (n = 21) and one resistance exercise group (n = 20). The experimental group performed three days of aerobic exercise and resistance exercise per week (i.e., Monday, Wednesday, and Friday) each group. Body composition, physical fitness, and myokines were measured at baseline, 6 weeks, and 12 weeks. Results Two-way within-factor ANOVA revealed group × time interaction for body mass index (BMI, P < 0.05). In the resistance exercise group, muscle endurance (P < 0.001), power (P < 0.01), and agility (P < 0.001) were significantly increased at 12 weeks than those at 6 weeks and baseline. In the aerobic exercise group, muscle strength (P < 0.05), flexibility (P < 0.05), muscle endurance (P < 0.001), and agility (P < 0.001) were greater at 12 weeks than those at 6 weeks and baseline. Levels of IL-6 (P < 0.001), IL15 (P < 0.001), and BDNF (P < 0.001) were greater at 12 weeks than those at 6 weeks and baseline in both exercise groups. Conclusions Aerobic exercise training and resistance exercise training can change levels of myokines and improve body composition and physical fitness of obese females. These findings provide preliminary evidence that obese females need to exercise or perform physical activity to improve their levels of myokines and physical fitness.