Purpose <p>This study investigated the acute physiological responses to a novel combined resistance training (CB) protocol—integrating isometric pre-exhaustion with low-load, high-velocity, short-arc isotonic contractions—and compared them with low-intensity slow training (LST) and high-load (HL) training.</p> Methods <p>Forty-eight healthy men were randomly assigned to one of three groups: LST (50% one-repetition maximum [1RM], slow tempo), HL (80% 1RM, normal tempo), or CB (40% 1RM; a 20-s isometric contraction followed by eight high-velocity, short-arc repetitions). Surface electromyography (EMG) and near-infrared spectroscopy (NIRS) of the vastus lateralis, alongside serum IGF-1 concentrations, were assessed during and following three leg-press sets.</p> Results <p>Despite utilizing a 40% 1RM load, the CB protocol elicited mean EMG amplitudes significantly greater than LST during the final set (<i>p</i> = 0.009, <i>g</i> = 1.23). NIRS analysis demonstrated a significantly lower change in tissue oxygen saturation (ΔStO₂) in the CB group compared to HL from the initial set (<i>p</i> = 0.001; <i>g</i> = 1.19), highlighting rapid intramuscular hypoxia. Furthermore, third-set integrated EMG was significantly higher in CB than in both HL (<i>p</i> = 0.002, <i>g</i> = 1.13) and LST (<i>p</i> &lt; 0.001, <i>g</i> = 1.63). Serum IGF-1 concentrations exhibited a significant post-exercise elevation across all groups (main effect of time: <i>p</i> &lt; 0.001, η_p² = 0.712).</p> Conclusion <p>By concurrently demanding high neural drive and inducing profound metabolic stress, the time-efficient CB protocol provides a robust physiological stimulus despite minimal mechanical loading. This approach serves as a practical, joint-friendly alternative for populations necessitating reduced mechanical stress.</p> Trial registration number <p>UMIN-CTR (UMIN000060486)</p> Graphical abstract <p></p>