Top‐class athletes have optimized their athletic performance largely through adequate training, nutrition, recovery, and sleep. A key component of sports nutrition is the utilization of nutritional ergogenic aids, which may provide a small but significant increase in athletic performance. Over the last decade, there has been an exponential increase in the consumption of nutritional ergogenic aids, where over 80% of young athletes report using at least one nutritional ergogenic aid for training and/or competition. Accordingly, due to their extensive use, there is a growing need for strong scientific investigations validating or invalidating the efficacy of novel nutritional ergogenic aids. Notably, an overview of the physiological considerations that play key roles in determining ergogenic efficacy is currently lacking. Therefore, in this brief review, we discuss important physiological considerations that contribute to ergogenic efficacy for nutritional ergogenic aids that are orally ingested including (1) the impact of first pass metabolism, (2) rises in systemic concentrations, and (3) interactions with the target tissue. In addition, we explore mouth rinsing as an alternate route of ergogenic efficacy that bypasses the physiological hurdles of first pass metabolism via direct stimulation of the central nervous system. Moreover, we provide real‐world examples and discuss several practical factors that can alter the efficacy of nutritional ergogenic aids including human variability, dosing protocols, training status, sex differences, and the placebo effect. Taking these physiological considerations into account will strengthen the quality and impact of the literature regarding the efficacy of potential ergogenic aids for top‐class athletes.