Objectives: To systematically review and analyse studies of high amounts of physical activity and mortality risk in the general population. Eligibility criteria: Inclusion criteria related to follow-up (minimum 2 years), outcome (mortality from all causes, cancer, cardiovascular disease (CVD) or coronary heart disease), exposure (eg, a category of >1000 metabolic equivalent of task (MET) min/week), study design (prospective cohort, nested case control or case-cohort) and reports of cases and person years of exposure categories. Information sources: Systematic searches were conducted in Embase and Pubmed from database inception to 2 March 2019. Risk of bias: The quality of the studies was assessed with the Newcastle-Ottawa scale. Included studies: From 31 368 studies identified, 48 were included. Two authors independently extracted outcome estimates and assessed study quality. Synthesis of results: We estimated hazard ratios (HRs) using random effect restricted cubic spline dose-response meta-analyses. Compared with the recommended level of physical activity (750 MET min/week), mortality risk was lower at physical activity levels exceeding the recommendations, at least until 5000 MET min/week for all cause mortality (HR=0.86, 95% CI 0.78 to 0.94) and for CVD mortality (HR=0.73, 95% CI 0.56 to 0.95). Strengths and limitations of evidence: The strengths of this study include the detailed dose-response analyses, inclusion of 48 studies and examination of sources of heterogeneity. The limitations include the observational nature of the included studies and the inaccurate estimations of amount of physical activity. Interpretation: Compared with the recommended level, mortality risk was lower at physical activity levels well above the recommended target range. Further, there was no threshold beyond which lifespan was compromised.