Purposeful weight loss continues to be the primary focus for treating obesity. However, this strategy appears to be inadequate as obesity rates continue to rise and a myriad of benefits of physical activity that affect multiple health outcomes related to obesity and associated comorbidities are not integrated into treatment strategies. There are emerging correlational data in individuals with obesity that demonstrate physical activity can be beneficial to many critical health markers, independent of weight loss or changes in BMI. This systematic review investigates interventional studies that examine health markers, independent of weight loss, in individuals with obesity. Fourteen studies were identified that utilized a variety of physical activity interventions with primary endpoints that included cellular, metabolic, systemic and brain health outcomes. The review of the literature demonstrates that for individuals with obesity, there are both small-scale and large-scale physiologic benefits that occur with increased physical activity of various modalities. Focusing on these benefits, rather than a narrow focus of weight loss alone, may increase physical activity behavior and health for individuals with obesity.