This study quantified performance and physiological responses during multi-set resistance exercise to failure at light versus moderate loads in normoxia and systemic hypoxia. On separate visits, fifteen resistance-trained adults performed barbell biceps curl exercise trials (6 sets to failure, 2 min rest between sets) in four separate randomised conditions; i.e. in normoxia at 380 m above sea level or systemic hypoxia at ∼3800 m simulated altitude (inspired oxygen fraction = 20.9% and 12.9%, respectively) combined with two different intensity levels (30% and 70% of 1 repetition maximal or 1RM). Muscle activation (root mean square value calculated from surface electromyography) and oxygenation (integrated-tissue saturation index derived from near-infrared spectroscopy) were monitored for the biceps brachii muscle. The total number of repetitions before failure at 30% 1RM (122 ± 5 vs. 131 ± 5; P = 0.021), but not 70% 1RM (39 ± 1 vs. 41 ± 2; P = 0.313), was lower in hypoxia compared to normoxia. Root mean square activity of the biceps brachii muscle was higher for 70% 1RM compared to 30% 1RM (P < 0.001), while the increase in muscle activation from the first to the last set (P < 0.001) occurred independently of altitude (P > 0.158). Deoxygenation and reoxygenation responses were higher under hypoxic versus normoxic conditions at 70% 1 RM (P = 0.013 and P = 0.015) but not 30% 1RM (P = 0.528 and P = 0.384). During upper-limb multi-set resistance exercise to failure, exposure to acute normobaric hypoxia negatively impacts performance at light, but not moderate, loads. Overall, external resistance has more profound effects on physiological strain than hypoxic exposure per se. Highlights The addition of acute systemic hypoxia negatively affects work performed at low, but not moderate, loads during upper-limb resistance exercise to failure. Hypoxic exposure, however, does not fundamentally alter muscle activation and oxygenation patterns. Muscle activation and oxygenation responses in turn are more largely influenced by load lifted.