Aim: Heat stress and hypoxia independently influence cerebrocortical activity and impair prolonged exercise performance. This study examined the relationship between electroencephalography (EEG) activity and self-paced exercise performance in control (CON, 18 °C, 40% RH), hot (HOT, 35 °C, 60% RH) and hypoxic (HYP, 18 °C, 40% RH FiO2: 0.145) conditions. Methods: Eleven well-trained cyclists completed a 750 kJ cycling time trial in each condition on separate days in a counterbalanced order. EEG activity was recorded with α- and β-activity evaluated in the frontal (F3 and F4) and central (C3 and C4) areas. Standardized low-resolution brain electromagnetic tomography (sLORETA) was also utilized to localize changes in cerebrocortical activity. Results: Both α- and β-activity decreased in the frontal and central areas during exercise in HOT relative to CON (P < 0.05). α-activity was also lower in HYP compared with CON (P < 0.05), whereas β-activity remained similar. β-activity was higher in HYP than in HOT (P < 0.05). sLORETA revealed that α- and β-activity increased at the onset of exercise in the primary somatosensory and motor cortices in CON and HYP, while only β-activity increased in HOT. A decrease in α- and β-activity occurred thereafter in all conditions, with α-activity being lower in the somatosensory and somatosensory association cortices in HOT relative to CON. Conclusion: High-intensity prolonged self-paced exercise induces cerebrocortical activity alterations in areas of the brain associated with the ability to inhibit conflicting attentional processing under hot and hypoxic conditions, along with the capacity to sustain mental readiness and arousal under heat stress.