Background: Stroke is not only an acute disease, but for the majority of patients, it also becomes a chronic condition. There is a major concern about the long-term follow-up with respect to activities of daily living (ADL) in stroke survivors. Some patients seem to be at risk for decline after a first-ever stroke. The purpose of this study was to determine the course of ADL from 3 months after the first-ever stroke and onward and identify factors associated with decline in ADL. Methods: A systematic literature search of 3 electronic databases through June 2015 was conducted. Longitudinal studies evaluating changes in ADL from 3 months post stroke onward were included. Cohorts including recurrent strokes and transient ischemic attacks were excluded. Regarding the course of ADL, a meta-analysis was performed using random-effects model. A best evidence synthesis was performed to identify factors associated with decline in ADL. Results: Out of 10,473 publications, 28 unique studies were included. A small but significant improvement in ADL was found from 3 to 12 months post stroke (standardized mean difference (SMD) 0.17 (0.04-0.30)), which mainly seemed to occur between 3 and 6 months post stroke (SMD 0.15 (0.05-0.26)). From 1 to 3 years post stroke, no significant change was found. Five studies found a decline in ADL status over time in 12-40% of patients. Nine factors were associated with ADL decline. There is moderate evidence for being dependent in ADL and impaired motor function of the leg. Limited evidence was found associated with insurance status, living alone, age ≥80, inactive state and having impaired cognitive function, depression and fatigue with decline in ADL. Conclusion: Although on an average patients do not seem to decline in ADL for up to 3 years, there is considerable variation within the population. Some modifiable factors associated with decline in ADL were identified. However, more research is needed before patients at risk of deterioration in ADL can be identified.