PURPOSE: How an acute training session of blood flow restriction (BFR) exercise affects autonomic modulation during a unilateral knee extension exercise. METHODS: Fourteen physically active males completed three different sessions while performing a unilateral knee extension exercise. The dependent variables measured: Heart rate variability (HRV), muscle oxygen saturation (SmO2), and rating of perceived exertion (RPE). Repeated measures ANOVAs were used to analyze HRV and SmO2 data. A paired t-test was used to analyze RPE data. RESULTS: Significant time-effect differences were found in lnRMSSD, lnHF, and lnLF at baseline to 15 minutes post-exercise and 15 to 30 minutes post-exercise (P < 0.05). Time and group-effect differences were significant in SmO2%, oxygenated, and deoxygenated hemoglobin in the vastus lateralis (VL) muscle in BFR compared to control (P < 0.05). RPE increased when BFR was applied (P < 0.05). CONCLUSION: Exercise protocol may need to be altered to show autonomic modulation changes.