Objectives: Insufficient physical activity is considered one of the leading causes of premature death worldwide. This study, therefore, aimed to investigate the effects of six weeks of moderate-intensity aerobic exercise on serum levels of Klotho, interleukin 10 (IL-10), IL-1, and oxidative stress in young women with a sedentary lifestyle. Materials and Methods: The present study was a semi-experimental study with a control group. Out of all volunteers, 20 young women eligible to participate in the study were selected and divided into the two groups (n=10) of experimental (i.e., six weeks of moderate-intensity aerobic exercise) and control (i.e., no exercise). Members of the experimental group performed an aerobic exercise program including running on a treadmill with an intensity of 55%-70% of their maximum heart rates (220-age). The running plan started with 50% of their maximum heart rates and reached 70% at the end of the six-week exercise program (three sessions per week). Paired t-test and independent t-test were conducted to examine intra-group and inter-group differences. All statistical procedures were performed using the SPSS version26 statistical package (P≤0.05). Results: At the beginning of the study, no significant difference was observed between the groups in terms of the markers. Six-week aerobic training increased Klotho (mean: 540, lower: 141.5, upper: 938.4) and IL-10 (mean: 0.43, lower: -1.56 upper: -0.47) in experimental group in comparison to control group (P=0.001). Six-week aerobic training decreased IL-1 (mean: 0.78, lower: -1.16 upper: -0.39) and H2O2 (mean: 0.41, lower: -0.96, upper: 0.12) in experimental group in comparison to control group (P=0.001). Conclusions: In sum, six-week moderate-intensity aerobic exercise program increased Klotho and IL-10 levels and decreased IL-1 and oxidative stress levels in young women with a sedentary lifestyle. According to these results, the decrease in oxidative stress and IL-1 levels due to exercise caused an increase in Klotho, and an increase in Klotho level, in turn, increased IL-10.