Previous research has shown that physical activity may mitigate the association between overweight/obesity and a number of negative health outcomes; however, less is known on how the duration of overweight/obesity alters this association. Therefore, the purpose of this leading article was to synthesize recent studies from our research group examining how physical activity, overweight/obesity classification, and importantly, overweight/obesity duration impact the association with a variety of different health outcomes. Five studies were analyzed, each of which used data from the National Health and Nutrition Examination Survey to analyze six mutually exclusive groups and their respective association with cardiovascular disease risk, all-cause mortality, multi-morbidity, health-related quality of life, and mild depressive symptoms. These studies detailed that physical inactivity, overweight/obesity classification, and overweight/obesity duration were each independently associated with cardiovascular disease risk and multi-morbidity. Additionally, physical activity reduced the risk of all-cause mortality across all weight classifications/durations, and also reduced the association with depressive symptoms and poor health-related quality of life among those overweight/obese for longer durations. These results illustrate that, while physical activity may reduce the association with negative health outcomes, overweight/obesity appears to increase this association independent of physical activity level, with this further exacerbated by the duration of overweight/obesity. Therefore, the emerging studies examining the importance of physical activity among overweight/obese individuals should also consider the duration of overweight/obesity as this will likely alter the associations present.