Both supplemental glucose and oxygen administration can improve aspects of cognitive performance. Previous research has established that more effortful cognitive processing results in reductions in peripheral blood glucose. We hypothesized that a similar phenomenon may be evident when measuring blood oxygen levels. This double-blind, placebo (air)-controlled, crossover study examined the effects of 100% oxygen administration and mental effort on heart rate and blood oxygen saturation. In counterbalanced order, twenty participants performed tasks where cognitive demand was relatively high (Serial Sevens) and relatively low (counting upwards) under conditions of normoxia and hyperoxia. Oxygen saturation and heart rates were comonitored using a pulse oximeter. Oxygen administration was associated with significantly fewer errors during Serial Sevens and the generation of more responses during counting. Both hyperoxia and heart rate were differentially affected by gas and task. Following oxygen inspiration, transient hyperoxia decayed significantly more rapidly during Serial Sevens than during the counting task. In the air condition, blood oxygen levels were raised during Serial Sevens compared with counting. The opposite effects were observed for heart rate. These results suggest that, following oxygen inspiration, a high cognitive load results in measurable uptake of circulating oxygen. This is likely to involve somatic and central processes.Journal of Cognitive Enhancement (2020) 4:94-99 https://doi.