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Background: Rheumatoid arthritis is an autoimmune disease that gradually destroys the synovial joints and leads to chronic inflammation. This autoimmune disorder is associated with an increase in stress-related symptoms, including anxiety and depression, and a decrease in social behaviors, which severely reduces the patient's quality of life. Previous studies show that higher physical activity during adolescence may lead to a decrease in neurobehavioral disorders in adulthood. This study was conducted with the aim of evaluating the increase of physical activity from early adolescence on stress-related behaviors and inflammation in mice with rheumatoid arthritis. Methods: Male mice were randomly exposed to a running wheel from early adolescence to adulthood, and then rheumatoid arthritis was induced. Stress-related behaviors, including anxiety, depression and social behavior were investigated in animals. The level of interleukin 17 (IL-17) and interferon gamma (IFN-γ) were also measured as important inflammatory markers in the serum. Results: The results showed that physical activity from early adolescence significantly resulted in decreased stress in mice with rheumatoid arthritis. In addition, the running wheel led to a decrease in the levels of (IL-17) and (IFN-γ) in rheumatoid arthritis-induced mice as two important indicators of inflammation. Conclusion: This study shows that increased physical activity during adolescence to adulthood may make mice resistant to increased stress and inflammation caused by rheumatic arthritis.