A systematic overview of mental and physical disorders of informal caregivers based on population-based studies with good methodological quality is lacking. Therefore, our aim was to systematically summarize mortality, incidence, and prevalence estimates of chronic diseases in informal caregivers compared to non-caregivers. Following PRISMA recommendations, we searched major healthcare databases (CINAHL, MEDLINE and Web of Science) systematically for relevant studies published in the last 10 years (without language restrictions) (PROSPERO registration number: CRD42020200314). We included only observational cross-sectional and cohort studies with low risk of bias (risk scores 0–2 out of max 8) that reported the prevalence, incidence, odds ratio (OR), hazard ratio (HR), mean- or sum-scores for health-related outcomes in informal caregivers and non-caregivers. For a thorough methodological quality assessment, we used a validated checklist. The synthesis of the results was conducted by grouping outcomes. We included 22 studies, which came predominately from the USA and Europe. Informal caregivers had a significantly lower mortality than non-caregivers. Regarding chronic morbidity outcomes, the results from a large longitudinal German health-insurance evaluation showed increased and statistically significant incidences of severe stress, adjustment disorders, depression, diseases of the spine and pain conditions among informal caregivers compared to non-caregivers. In cross-sectional evaluations, informal caregiving seemed to be associated with a higher occurrence of depression and of anxiety (ranging from 4 to 51% and 2 to 38%, respectively), pain, hypertension, diabetes and reduced quality of life. Results from our systematic review suggest that informal caregiving may be associated with several mental and physical disorders. However, these results need to be interpreted with caution, as the cross-sectional studies cannot determine temporal relationships. The lower mortality rates compared to non-caregivers may be due to a healthy-carer bias in longitudinal observational studies; however, these and other potential benefits of informal caregiving deserve further attention by researchers.