The effect of creatine supplementation and sleep deprivation, with intermittent moderate-intensity exercise, on cognitive and psychomotor performance, mood state, effort and salivary concentrations of cortisol and melatonin were examined. Subjects were divided into a creatine supplementation group and a placebo group. They took 5 g of creatine monohydrate or a placebo, dependent on their group, four times a day for 7 days immediately prior to the experiment. They undertook tests examining central executive functioning, short-term memory, choice reaction time, balance, mood state and effort at baseline and following 18-, 24- and 36-h sleep deprivation, with moderate intermittent exercise. Saliva samples were taken prior to each set of tests. A group x time analysis of covariance, with baseline performance the covariate, showed that the creatine group performed significantly (p < 0.05) better than the placebo group on the central executive task but only at 36 h. The creatine group demonstrated a significant (p < 0.01) linear improvement in performance of the central executive task throughout the experiment, while the placebo group showed no significant effects. There were no significant differences between the groups for any of the other variables. A significant (p < 0.001) main effect of time was found for the balance test with a linear improvement being registered. Cortisol concentrations on Day 1 were significantly (p < 0.01) higher than on Day 2. Mood significantly (p < 0.001) deteriorated up to 24 h with no change from 24 to 36 h. Effort at baseline was significantly (p < 0.01) lower than in the other conditions. It was concluded that, during sleep deprivation with moderate-intensity exercise, creatine supplementation only affects performance of complex central executive tasks.