South Asia specific reviews on the role of physical activity (PA) domains on chronic disease prevention are lacking. This study aimed to systematically review published literature to identify the association between PA domains and chronic diseases and to provide summary estimates of the strength of association. Nine electronic databases were searched using the predefined inclusion criteria which included population (South Asian adults 40 years or older), exposure (PA or sedentary behaviour) and outcome (type 2 diabetes mellitus, breast cancer, colorectal cancer, coronary heart disease, stroke, vascular disease and musculoskeletal diseases and their markers). A random-effects meta-analysis was carried out for cardiometabolic outcomes whereas narrative synthesis was completed for other outcome variables. Inactive or less active South Asian adults were at 31% higher risk of being hypertensive. Likewise, the risk of cardiometabolic outcomes was 1.34 times higher among inactive adults. Household PA was found to have a protective effect on breast cancer risk. Total and leisure time PA had a protective effect on osteoporosis among males and females respectively. Contemporary studies with a longitudinal design, representative samples, valid and reliable assessment of different domains are needed to establish the role of PA in chronic disease prevention in the region.