Due to an increasing elderly population coupled with a growing obesity epidemic, there has been an increased prevalence in cardiovascular and musculoskeletal diseases. This has led to an increased burden in healthcare expenditures, now estimated to be over 17.8% of gross domestic product. As a result, physical activity has been increasingly encouraged due to its potential prophylactic effects on health. Recent reports have demonstrated a relationship between physical activity and body mass index (BMI) on cardiovascular and musculoskeletal health. However, the effect of the combination of the two have not been reported. Therefore, the purpose of this review was to assess the effect of various levels of physical activity on: 1) cardiovascular disease risk; and 2) the development of musculoskeletal disease (osteoarthritis [OA]) when accounting for various levels of BMIs. A total of 143 abstracts were identified for cardiovascular health and 55 abstracts for musculoskeletal health. Upon review, 11 reports were included for final evaluation. Despite patient BMI, physical activity was associated with a decreased risk of cardiovascular events. Additionally, moderate levels of physical activity were demonstrated to be protective against the development of OA; however, the levels of physical activity necessary to be beneficial were not fully elucidated. This suggests that the prophylactic effects of physical activity were maintained despite patient BMI. Future studies are needed to explore the appropriate levels of physical activity for optimal effectiveness when stratifying by patient BMI.