Background: Covid-19 is considered a new disease across the globe. Physical activity reduces risk factors, and with anti-inflammatory and antioxidant properties, saffron is used as a traditional herbal medicine to treat cough and asthma. Therefore, the present study aimed to assess the effect of saffron supplementation and endurance training on the concentration of C-reactive protein, interleukin-8, and clinical symptoms in outpatients with COVID-19. Materials and Methods: The present research was conducted based on a randomized, double-blind, four-group, pretest-posttest design. The statistical population of this research entailed all outpatients with COVID-19 referred to the health center of Keshkosrai. Among this population, 36 cases were randomly selected. The research hypotheses were evaluated using SPSS software at a significance level of P<0.05 using the statistical test of analysis of covariance (ANCOVA) and paired T-test. Results: The results of ANCOVA demonstrated that after adjusting the effect of baseline values, height, and body mass index, there was a statistically significant difference between the groups in terms of the mean change of interleukin-8, C-reactive protein, partial oxygen pressure (SpO2), and body temperature (P<0.05). That is, the type of intervention can markedly affect the change of interleukin-8, C-reactive protein, partial oxygen pressure, and body temperature. Conclusion: As evidenced by the obtained results, it is possible to use saffron as an auxiliary therapeutic method, as well as regular sports activity, which helps to control pathogens, including COVID-19, by boosting the body's immunity.