Low‐load blood‐flow‐restriction resistance training (LL‐BFR‐RT) is gaining popularity, but its physiological effects remain unclear. This study aimed to compare LL‐BFR‐RT with low‐load resistance exercise (LL‐RT) and high‐load resistance exercise (HL‐RT) on metabolism, electrolytes, and ions in the lower extremities by invasive catheter measurements, which are crucial for risk assessment. Ten healthy men (27.6 ± 6.4 years) completed three trials of knee‐extensor exercises with LL‐RT (30% 1RM), LL‐BFR‐RT (30% 1RM, 50% limb occlusion pressure), and HL‐RT (75% 1RM). The exercise protocol consisted of four sets to voluntary muscle failure with 1 min of rest between sets. Blood gas analysis was collected before, during, and after each trial through intravenous catheters at the exercising leg. LL‐BFR‐RT had lower total workload (1274 ± 237 kg, mean ± SD) compared to LL‐RT (1745 ± 604 kg), and HL‐RT (1847 ± 367 kg, p < 0.01), with no difference between LL‐RT and HL‐RT. Pain perception did not differ significantly. Exercise‐induced drop in oxygen partial pressure, lactate accumulation and electrolyte shifts (with increased [K+]) occurred during under all conditions (p < 0.001). Creatine kinase and lactate dehydrogenase increased significantly 24‐ and 48‐h postexercise under all three conditions (p < 0.001). This study, using invasive catheter measurements, found no significant differences in metabolic, ionic, and electrolyte responses among LL‐BFR‐RT, LL‐RT, and HL‐RT when exercised to voluntary muscular failure. LL‐BFR‐RT reduced time to failure without specific physiological responses.