The impact of caffeine and glucose supplementation in a hypoxic environment on endurance exercise performance remains inconclusive. The current study examined the effect of pre-exercise carbohydrate and caffeine supplementation on endurance exercise performance in an acute hypoxic environment. Eight healthy active young males participated in this double-blind, within-subjects crossover study. Participants ingested the test drink 60 min before exercising at 50% Wmax for 90 min on a cycle ergometer (fatiguing preload); there followed an endurance performance test at 85% Wmax until exhaustion in a hypoxic chamber (~15%O2). Participants completed four experimental trials in a randomized order: caffeine (6 mg·kg−1; Caff), glucose (1 g·kg−1; CHO), caffeine (6 mg·kg−1) + glucose (1 g·kg−1; Caff−CHO), and taste- and color-matched placebo with no caffeine or CHO (PLA). Blood samples were collected during fasting, pre-exercise, every 30 min throughout the exercise, and immediately after exhaustion. The caffeine and glucose trials significantly enhanced endurance capacity in hypoxic conditions by Caff, 44% (68.8–31.5%, 95% confidence interval), CHO, 31% (44.7–15.6%), and Caff−CHO, 46% (79.1–13.2%). Plasma-free fatty-acid and glycerol concentrations were higher in Caff and PLA than in CHO and Caff−CHO (p < 0.05). The estimated rate of fat oxidation was higher in Caff and PLA than in CHO and Caff−CHO (p < 0.05). There were no significant differences in ratings of perceived exertion between trials. In conclusion, the ingestion of caffeine, glucose, or caffeine + glucose one hour before exercising in hypoxic conditions significantly improved 85% Wmax endurance performance after prolonged exercise.