Background: The mTOR signaling pathway and its related genes are activated by resistance training and cause muscle hypertrophy. On the other hand, renal hypertrophy is usually associated with some kidney disorders and diseases. In the meantime, spirulina supplement also participates in the process of making protein and increases protein synthesis. Aim: The purpose of this study was to investigate the effect of gene expression changes (TNF-α/IKKβ/TSC1/Rheb) in the kidney tissue of male rats; Emphasis was on exercise along with spirulina supplementation. Methodology: In order to conduct this research, 32 young male Wistar rats (12±2 weeks, 250±50 g) were prepared and randomly divided into four groups of 8 rats of: Spirulina, resistant training, exercise+ Spirulina and control. The resistance training protocol consisted of eight weeks of climbing the rodent ladder at a height of one meter, which was performed every other day and three to four repetitions per session. The Spirulina group also received 300 mg/kg/day Spirulina supplement dissolved in drinking water for 8 weeks. Data were analyzed using two-way analysis of variance and Tukey's post hoc test. Findings: The findings showed that compared to the control group, TNF-α gene expression in the resistance training group increased significantly (p<0.05), the spirulina group decreased significantly (p<0.05), and the combined group remained unchanged (p>0.05). Also, compared to the control group, resistant training and the combination of training and supplementation led to a significant increase in IKKβ gene expression (p<0.05). Compared to the control group, TSC1 gene expression increased significantly in all three groups, and the spirulina group showed the highest increase (p<0.05). Rheb gene expression in all three groups showed a slight and insignificant increase (p>0.05). Conclusion: Based on the results of the present research, spirulina supplementation alone has no effect on the signaling pathway of kidney hyper