Introduction: Exercise is one of the recommended factors to reduce mortality from all types of cancer, especially brain cancer. The purpose of this study was to investigate the changes in the expression of Paxillin and PTK2 genes in the brain tissue of rats with glioblastoma multiforme after aerobic exercise training. Materials and Methods: Twenty-four male Wistar rats were divided into three groups (n=8): Healthy control, brain tumor, and tumor + aerobic training (AT). Glioblastoma was injected into frontal cortex of rats' brain. The exercise group performed aerobic exercises on the treadmill for four weeks and three days per week at a speed of 18 meters per minute for 25 to 40 minutes. At the end, the rats were sacrificed and Paxillin and PTK2 genes of their brain tissue were analyzed by Real-time PCR method. Histological images with H&E method were also used to confirm the tumor. Results: The tumor group showed increased necrosis and brain tissue damage compared to the healthy control group. In addition, the tumor group showed a significant increase in the expression of Paxillin and PTK2 genes compared to the healthy control group (p<0.001). This was while doing aerobic exercise in animals with brain tumor caused a significant decrease in Paxillin and PTK2 compared to the tumor group (p<0.001). Conclusion: Performing aerobic exercise in animals with brain tumors can reduce tumor cell strength by reducing the expression of Paxillin and PTK2 genes (effective in the extracellular matrix). However, more studies are needed in this field.