Introduction: Blood flow restriction (BFR) has been shown to induce local hypoxia. Therefore, the purpose of this study was to investigate the effect of BFR-induced hypoxia on the angiogenic response to high-intensity interval exercise (HIIE). Methods: Thirty active young men (age =25.6±3.4) were randomly assigned to three groups (n=10 each): control, high-intensity interval exercise (HIIE), and high-intensity interval exercise with blood flow restriction (HIIE+BFR). The HIIE protocol consisted of 5 sets of 5×30-second high-intensity running intervals with 30-second rest periods. BFR was applied at 60% of each individual's optimal occlusion pressure in the lower limbs. Serum levels of VEGF, HIF-1α, MMP-9, and MMP-2 were measured as angiogenic markers. Statistical analysis was performed using ANCOVA with LSD post-hoc test, with the significance level set at α=0.05. Results: The data revealed that compared to both the control and HIIE groups, the HIIE+BFR group showed significantly greater increases in serum VEGF and HIF-1α levels (P=0.002 and P=0.019, respectively). However, no significant differences were observed among groups for MMP-9 and MMP-2 levels (P=0.318 and P=0.101, respectively). Conclusion: This study demonstrated that combining HIIE with BFR can enhance the angiogenic response through increased VEGF and HIF-1α levels, but does not significantly affect MMP-2 and MMP-9. These findings support the notion that BFR-induced local hypoxia may serve as a complementary stimulus for improving vascular adaptations.