Purpose: To investigate whether performing resistance exercise in hypoxia augments physiological and perceptual responses, and if altering work-rate by performing repetitions to failure compared to sub-maximally increases the magnitude of these responses. Methods: Twenty male university students (minimum of 2 year resistance training experience) completed four sessions, two in hypoxia (fraction of inspired oxygen [FiO2] = 0.13), and two in normoxia (FiO2 = 0.21). For each condition, session one comprised three sets to failure of shoulder press and bench press (high work-rate session), while session two involved the same volume load, distributed over six sets (low work-rate session). Muscle oxygenation (triceps brachii), surface electromyographic activity (anterior deltoid, pectoralis major, and triceps brachii), heart rate (HR), and arterial blood oxygen saturation were recorded. Blood lactate concentration ([Bla−]) was recorded pre-exercise and 2 min after each exercise. Muscle thickness was measured pre- and post-exercise via ultrasound. Results: Muscle oxygenation values during sets and inter-set rest periods were lower in hypoxia vs normoxia (p = 0.001). Hypoxia caused greater [Bla−] during the shoulder press of failure sessions (p = 0.003) and both shoulder press (p = 0.048) and bench press (p = 0.005) of non-failure sessions. Hypoxia increased HR during non-failure sessions (p < 0.001). There was no effect of hypoxia on muscular swelling, surface electromyographic activity, perceived exertion, or number of repetitions performed. Conclusions: Hypoxia augmented metabolite accumulation, but had no impact on any other physiological or perceptual response compared to the equivalent exercise in normoxia. Furthermore, the magnitude to which hypoxia increased the measured physiological responses was not influenced by sessional work-rate.