Purpose: This study investigated the effect of ischemic preconditioning (IP) on metaboreflex activation following dynamic leg extension exercise in a group of healthy participants. Method: Seventeen healthy participants were recruited. IP and SHAM treatments (3 × 5 min cuff occlusion at 220 mmHg or 20 mmHg, respectively) were administered in a randomized order to the upper part of exercising leg’s thigh only. Muscle pain intensity (MP) and pain pressure threshold (PPT) were monitored while administrating IP and SHAM treatments. After 3 min of leg extension exercise at 70% of the maximal workload, a post-exercise muscle ischemia (PEMI) was performed to monitor the discharge group III/IV muscle afferents via metaboreflex activation. Hemodynamics were continuously recorded. MP was monitored during exercise and PEMI. Results: IP significantly reduced mean arterial pressure compared to SHAM during metaboreflex activation (mean ± SD, 109.52 ± 7.25 vs. 102.36 ± 7.89 mmHg) which was probably the consequence of a reduced end diastolic volume (mean ± SD, 113.09 ± 14.25 vs. 102.42 ± 9.38 ml). MP was significantly higher during the IP compared to SHAM treatment, while no significant differences in PPT were found. MP did not change during exercise, but it was significantly lower during the PEMI following IP (5.10 ± 1.29 vs. 4.00 ± 1.54). Conclusion: Our study demonstrated that IP reduces hemodynamic response during metaboreflex activation, while no effect on MP and PPT were found. The reduction in hemodynamic response was likely the consequence of a blunted venous return.