Background: A growing body of studies that investigated the longitudinal association between physical activity (PA) and the outcome of incident obesity, coronary heart disease (CHD), diabetes and hypertension has become available in recent years. Thus, the purpose of this systematic review was to provide an update on the association between PA and onset of obesity, CHD, diabetes and hypertension in individuals aged ≥18 years who were free of the respective conditions at baseline. Methods: We systematically searched OVID, Pubmed, and Web of Science databases for pertinent literature published between January of 2012 and February of 2019. To ensure that conclusions are based on high quality evidence, we only included longitudinal studies conducted in samples of ≥500 participants and with ≥5 years of follow-up. Result: The search yielded 8929 records of which 26 were included in this review. Three studies were conducted on the outcome of incident obesity, eight on incident CHD, nine on incident diabetes, four on incident hypertension, one on the outcome of both diabetes and hypertension, and one on the outcome of CHD, diabetes and hypertension. Overall, there was an association between PA and lower risk of incident obesity, CHD and diabetes, but not hypertension. Higher levels or amount of PA were associated with a reduced risk of new onset of the respective diseases in 20 studies (77%). Whereas four studies reported an elevated risk of incidence of diseases with lower PA levels (15%). PA was not associated with incidence of diseases in two studies (8%).