Abstract Background Physical activity, sedentary behaviour and sleep are interrelated and may have a synergistic impact on health. This systematic review and meta-analysis of prospective cohort studies aimed to evaluate the combined influence of different combinations of these behaviours on mortality risk and incidence of cardiovascular disease (CVD), cancer, diabetes, and mental health. Methods Four online databases were used to identify studies from database inception to May 2023. Prospective cohort studies that examined how different combinations of physical activity, sedentary and sleep behaviours were associated with mortality and incident cardiovascular disease, cancer, diabetes and mental health in adults were included. Random effects meta-analyses using the Der Simonian and Laird method were conducted. Results Assessment of 4583 records resulted in twelve studies being included. Studies were qualitatively summarised and a sub-group of studies (n = 5) were meta-analysed. The most frequent combination of behaviours was duration of leisure time physical activity and sleep (n = 9), with all-cause mortality (n = 16), CVD mortality (n = 9) and cancer mortality (n = 7) the most frequently examined outcomes. Meta-analysis revealed that relative to High physical activity & Mid sleep, High physical activity and Short sleep was not associated with risk of all-cause mortality (RR = 1.05, 95% CI = 0.97, 1.14), however Low physical activity and Short Sleep (RR = 1.42, 95% CI = 1.24, 1.63), Low physical activity and Mid Sleep (RR = 1.30, 95% CI = 1.12, 1.52), High physical activity and Long Sleep (RR = 1.16, 95% CI = 1.01, 1.32), and Low physical activity and Long Sleep were associated with risk of all-cause mortality (RR = 1.63, 95% CI = 1.21, 2.20). Conclusions High levels of physical activity may offset all-cause mortality risks associated with short sleep duration. Low levels of physical activity combined with short sleep duration and any level of physical activity in combination with long sleep duration appear to increase mortality risk. Currently there is limited evidence regarding how dimensions of physical activity, sedentary and sleep behaviours other than duration (e.g., quality, timing, type) are associated with future health status.