PURPOSE: The importance of the brain in sports was recently confirmed by the negative effect of mental fatigue (MF) on sport-specific psychomotor skills. Creatine supplementation improves strength but can also improve cognitive functioning. To explore the role of creatine in combating MF, we evaluated whether creatine supplementation counteracts the MF-associated impairment in sport-specific psychomotor skills. METHODS: In 23°C, 14 healthy participants (4 females, 10 males; mean ± SD, age = 24 ± 3 yr, mass = 74 ± 13 kg, height = 179 ± 9 cm) performed a 90-min mentally fatiguing task (counterbalanced, crossover, and double-blinded; i.e., Stroop task) in two different conditions: after a 7-d creatine supplementation (CR; 20 g·d) and after a 7-d calcium lactate supplementation (placebo [PLAC]), separated by a 5-wk washout. In both conditions, a 7-min sport-specific visuomotor task, a dynamic handgrip strength endurance task, and a 3-min Flanker task was performed before and after the mentally fatiguing task. Physiological and perceptual responses were measured throughout the protocol. RESULTS: Handgrip strength endurance was higher in CR compared with PLAC (P = 0.022). MF impaired visuomotor response time (+4.4%; P = 0.022) and Flanker accuracy (-5.0%; P = 0.009) in both conditions. Accuracy on the Stroop task was higher in CR compared with PLAC (+4.9%; P = 0.026). Within the perceptual and physiological parameters, only motivation and vigor (P ≤ 0.027) were lower in CR compared with PLAC. CONCLUSION: Creatine supplementation improved physical (strength endurance) and prolonged cognitive (Stroop accuracy) performance, yet it did not combat MF-induced impairments in short sport-specific psychomotor or cognitive (Flanker) performance. These results warrant further investigation in the potential role of creatine in combating the MF-associated decrements in prolonged (e.g., 90-min soccer game) sport performance and suggest a role of brain phosphocreatine in MF.