Two of the most actively studied modifiable lifestyle factors, exercise and video gaming, are regularly touted as easy and effective ways to enhance brain function and/or protect it from age-related decline. However, some critical lingering questions and methodological inconsistencies leave it unclear what aspects of brain health are affected by exercise and video gaming, if any at all. In a global online study of over 1000 people, we collected data about participants' physical activity levels, time spent playing video games, mental health, and cognitive performance using tests of short-term memory, verbal abilities, and reasoning skills from the Creyos battery. The amount of regular physical activity was not significantly related to any measure of cognitive performance; however, more physical activity was associated with better mental health as indexed using the PHQ-2 and GAD-2 screeners for depression and anxiety. Conversely, we found that more time spent playing video games was associated with better cognitive performance but was unrelated to mental health. We conclude that exercise and video gaming have differential effects on the brain, which may help individuals tailor their lifestyle choices to promote mental and cognitive health, respectively, across the lifespan.