This study examined whether hypoxia during multi-set, high-load resistance exercise alters neuromuscular responses. Using a single-blinded (participants), randomised crossover design, eight resistance-trained males completed five sets of five repetitions of bench press at 80% of one repetition maximum in moderate normobaric hypoxia (inspiratory oxygen fraction = 0.145) and normoxia. Maximal isometric bench press trials were performed following the warm-up, after 10 min of altitude priming and 5 min post-session (outside, inside and outside the chamber, respectively). Force during pre-/post-session maximal voluntary isometric contractions and bar velocity during exercise sets were measured along with surface electromyographic (EMG) activity of the pectoralis major, anterior deltoid and lateral and medial triceps muscles. Two-way repeated measures ANOVA (condition×time) were used. A significant time effect (p = 0.048) was found for mean bar velocity, independent of condition (p = 0.423). During sets of the bench press exercise, surface EMG amplitude of all studied muscles remained unchanged (p > 0.187). During maximal isometric trials, there were no main effects of condition (p > 0.666) or time (p > 0.119), nor were there any significant condition×time interactions for peak or mean forces and surface EMG amplitudes (p > 0.297). Lower end-exercise blood oxygen saturation (90.9 ± 1.8 vs. 98.6 ± 0.6%; p < 0.001) and higher blood lactate concentration (5.8 ± 1.4 vs. 4.4 ± 1.6 mmol/L; p = 0.007) values occurred in hypoxia. Acute delivery of systemic normobaric hypoxia during multi-set, high-load resistance exercise increased metabolic stress. However, only subtle neuromuscular function adjustments occurred with and without hypoxic exposure either during maximal isometric bench press trials before versus after the session or during actual exercise sets. Highlights Performing multi-set, high-load bench press resistance exercise in hypoxia accentuates metabolic stress, as evidenced by lower arterial oxygen saturation and higher blood lactate concentration, compared to normoxia. Acute hypoxic exposure doesn’t alter neuromuscular responses during the execution of the sets since mean bar velocity dropped similarly in both conditions from set 2 to set 5 with no difference in peak velocity and surface EMG amplitude of the prime movers during the bench press. Only subtle adjustments in peak or mean force and accompanying surface EMG activity occur with and without hypoxic exposure during maximal isometric bench press trials after a 10-min hypoxic priming period and 5 min after the session in reference to post-warm-up.