We aimed to examine the association of weight gain during adulthood with the risk of cardiovascular disease (CVD) in the general population. We performed a systematic search of PubMed and Scopus, from inception to June 2019. Prospective cohort studies investigating the association of weight gain during adulthood with the risk of CVD were included. The relative risks (RRs) were calculated by using random-effect models. Twenty-three prospective cohort studies with 1,093,337 participants were included. The RRs for a 5-kg increment in body weight were 1.11 (95% CI: 1.04, 1.19; I2 = 80%, n = 11) for CVD mortality, 1.18 (95% CI: 1.04, 1.32; I2 = 90%, n = 8) for coronary heart disease (CHD), 1.08 (95% CI: 1.04, 1.12; I2 = 0%, n = 3) for stroke, 1.18 (95% CI: 1.12, 1.25; I2 = 0%, n = 2) for myocardial infarction and 1.05 (95% CI: 0.86, 1.23; I2 = 80%, n = 2) for heart failure. A dose-response analysis demonstrated that the risk of CVD mortality was unchanged with weight gain of 0-5 kg, and then increased sharply and linearly (P for nonlinearity < 0.001). The analysis of CHD indicated a sharp increase in risk from baseline up to weight gain equal to 25 kg (P for nonlinearity = 0.12). Adult weight gain may be associated with a higher risk of CVD. Measuring weight gain during adulthood may be better than static, cross-sectional assessment of weight because it considers trend over time, and thus, can be used as a supplementary approach to predict CVD.