A large and growing body of research shows that non-caffeinated plant-based nutritional supplements can increase cognitive and physical performance. This study aimed to build on this work by investigating the possibility that a specific botanical blend (consisting of Bacopa monnieri bacosides, Kaempferia parviflora methoxy flavones, pomegranate peel polyphenols, and Moringa oleifera leaf saponins) could improve cognitive and physical performance. To this end, we carried out a randomized, double-blind, placebo-controlled 21-day parallel study on 36 healthy adults. We compared the effects of the botanical blend at baseline to a caffeine and a placebo condition on 1) self-reported alertness, anxiety, and headaches; 2) multiple measures of attention and cognition; 3) physical performance; and 4) stress biomarkers. We found that relative to baseline and compared to the Caffeine and Placebo groups, the botanical blend increased alertness and improved cognitive performance. The cognitive effects were most robust for attention measures. The botanical blend did not improve physical performance on a time to exhaustion (TTE) test. Of note, there was not the expected increase in catecholamine response after the TTE on Day 21, suggesting that long-term botanical blend use decreases the catecholamine stress response of a physical endurance task. In conclusion, we show that, within the confines of this study, a combination of the botanical blend could serve as a safe and effective nutritional supplement to improve cognitive performance.