Introduction: Regular exercise or increasing physical activity have been proven that lower the risk of cardiovascular diseases. However, recently evidences indicated acute vigorous or high-intensity exercises have been shown transiently increased the risk of vascular thrombotic events. Both Rhodiola crenulata (R) and Cordyceps sinensis (C) supplements has been widely applied to health food market for improving individual quality of life and promoting human health. Limited studies address the beneficial effects of combining Rhodiola crenulata and Cordyceps sinensis (RC) on reducing systemic inflammation and coagulation in sedentary adults after acute vigorous cycling exercise. Methods: A randomized double-blind and crossover experimental design was conducted in this study. Twelve healthy sedentary individuals (age: 21.4 ± 0.4 years, height: 170.3 ± 6.1 cm, weight: 67.3 ± 13.6 kg) were received either RC (20 mg/kg) or placebo for 7 days. All participants were performed an hour cycling exercise challenge with 75% VO2max intensity. Blood sample collection was conducted at pre-exercise and immediately of one-hour exercise challenge. The HRV measurement was performed at pre-exercise and two hours after exercise challenge. Blood samples were used to analysis the systemic inflammation response (neutrophil/lymphocyte, NLR), and coagulation markers (i.e., fibrinogen, PT, APTT). There was spaced 7 days apart between trials. Results: The change of fibrinogen, NLR and sympathetic nerve activity in RC trial were significantly lowered than in placebo trial after an hour vigorous exercise challenge. Moreover, the change of total power was observed significantly higher in RC trial than in placebo following exercise. No significant difference in parasympathetic nerve activity between trials. Conclusion: Our study demonstrates that provision of an RC supplement provides greater protective effects in attenuating blood coagulation after a vigorous exercise. These benefits from RC treatment might be due to reduce systemic inflammatory response and sympathetic nerve activity following exercise challenge.