Weight loss and weight loss maintenance are prominent topics of discussion for clinicians and health professionals involved in treatment to reduce obesity and the risk of cardiovascular disease. Because physical activity is a key component of comprehensive obesity treatment, this scientific statement summarizes the role of physical activity in promoting weight loss, weight loss maintenance, and cardiometabolic health, complementing lifestyle, pharmacological, and surgical-based weight loss intervention strategies. Independently of weight loss, physical activity and exercise programs improve major cardiometabolic risk factors, including hypertension, insulin resistance, and dyslipidemia, which are highly prevalent in patients with overweight or obesity. As a single treatment modality, physical activity and exercise programs are unlikely to result in clinically meaningful weight loss (ie, at least 5% loss of initial body weight) unless aerobic physical activity levels are exceptionally high. When combined with diet-induced negative energy balance, obesity medication, or surgical treatment, increased physical activity can augment total weight loss and improve cardiometabolic outcomes. Because clinicians and health professionals play a pivotal role in fostering and sustaining patients' health goals, this scientific statement also provides an overview of evidence-based strategies for targeted weight loss counseling and for leveraging digital technology, particularly to engage patients and achieve realistic physical activity goals.