Objective: Mask plays an important role in preventing infectious respiratory diseases. The influence of wearing masks in physical exercise on the human body needs to be studied. The purpose of this study is to explore the influence of wearing surgical masks on the cardiopulmonary function of healthy people during exercise. Methods: The physiological responses of 71 healthy subjects (35 men and 36 women, age 27.77 ± 7.76 years) to exercises with and without surgical masks (mask-on and mask-off) were analyzed. Cardiopulmonary function and metabolic reaction were measured by the cardiopulmonary exercise test (CPET). All tests were carried out in random sequence and should be completed in 1 week. Results: The CPETs with the mask-on condition were performed undesirably (p < 0.05), and the Borg scale was higher than the mask-off (p < 0.001). Rest oxygen uptake ( V . O 2 ) and carbon dioxide production ( V . CO2) with the mask-on condition were lower than mask-off (p < 0.01), which were more obvious at peak exercise ( V . O2 peak : 1454.8 ± 418.9 vs. 1628.6 ± 447.2 ml/min, p < 0.001; V . CO2 peak : 1873.0 ± 578.7 vs. 2169.9 ± 627.8 ml/min, p = 0.005), and the anaerobic threshold (AT) brought forward (p < 0.001). At different stages of CPET with the mask-on condition, inspiratory and expiratory time (Te) was longer (p < 0.05), and respiratory frequency (Rf) and minute ventilation ( V . E ) were shorter than mask-off, especially at peak exercise (Rf peak : 33.8 ± 7.98 vs. 37.91 ± 6.72 b/min, p < 0.001; V . Epeak : 55.07 ± 17.28 vs. 66.46 ± 17.93 l/min, p < 0.001). V T was significantly lower than mask-off just at peak exercise (1.66 ± 0.45 vs. 1.79 ± 0.5 l, p < 0.001). End-tidal oxygen partial pressure (PetO2), end-tidal carbon dioxide partial pressure (PetCO2), oxygen ventilation equivalent ( V . E / V . O2), and carbon dioxide ventilation equivalent ( V . E / V . CO2) with mask-on, which reflected pulmonary ventilation efficiency, were significantly different from mask-off at different stages of CPET (p < 0.05), but no significant difference in percutaneous oxygen saturation (SpO2) was found. Differences in oxygen pulse ( V . O2/HR), oxygen uptake efficiency slope (OUES), work efficiency (△ V . O2/△W), peak heart rate (HR), and peak systolic blood pressure (BP) existed between two conditions (p < 0.05). Conclusion: Wearing surgical masks during aerobic exercise showed certain negative impacts on cardiopulmonary function, especially during high-intensity exercise in healthy young subjects. These results provide an important recommendation for wearing a mask at a pandemic during exercises of varying intensity. Future research should focus on the response of wearing masks in patients with related cardiopulmonary diseases.