Heat and hypoxia exacerbate central nervous system (CNS) fatigue. We therefore investigated whether essential amino acid (EAA) and caffeine ingestion attenuates CNS fatigue in a simulated team sport–specific running protocol in a hot, hypoxic environment. Subelite male team sport athletes (n = 8) performed a repeat sprint running protocol on a nonmotorized treadmill in an extreme environment on 4 separate occasions. Participants ingested one of four supplements: a double placebo, 3 mg.kg⁻¹ body mass of caffeine + placebo, 2 × 7 g EAA (Musashi Create)+placebo, or caffeine + EAA before each exercise session using a randomized, double-blind crossover design. Electromyography (EMG) activity and quadriceps evoked responses to magnetic stimulation were assessed from the dominant leg at preexercise, halftime, and postexercise. Central activation ratio (CAR) was used to quantify completeness of quadriceps activation. Oxygenation of the prefrontal cortex was measured via near-infrared spectroscopy. Mean sprint work was higher (M = 174 J, 95% CI [23, 324], p < .05, d = 0.30; effect size, likely beneficial) in the caffeine + EAA condition versus EAAs alone. The decline in EMG activity was less (M = 13%, 95% CI [0, 26]; p < .01, d = 0.58, likely beneficial) in caffeine + EAA versus EAA alone. Similarly, the pre- to postexercise decrement in CAR was significantly less (M = −2.7%, 95% CI [0.4, 5.4]; p < .05, d = 0.50, likely beneficial) when caffeine + EAA were ingested compared with placebo. Cerebral oxygenation was lower (M = −5.6%, 95% CI [1.0, 10.1]; p < .01, d = 0.60, very likely beneficial) in the caffeine + EAA condition compared with LNAA alone. Coingestion of caffeine and EAA appears to maintain muscle activation and central drive, with a small improvement in running performance.