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.