Purpose The purpose of the study is to conduct a systematic review of studies examining the association between anticholinergic burden and mortality in older individuals. Methods A literature search was performed to identify relevant studies, using MEDLINE, EMBASE, PsycINFO and CENTRAL, from January 1990 to December 2018. We included studies of patients with a mean age of 65 years or older where the anticholinergic burden was estimated using anticholinergic risk assessment tools, and associations between anticholinergic load and mortality were investigated. The primary outcome of interest was the association between anticholinergic burden and mortality. Results Twenty-seven studies were included. These were three cross-sectional, one nested case-control and 23 prospective or retrospective cohort studies. Most studies were determined to be of good quality. A total of 15 studies reported a positive correlation between anticholinergic burden and mortality, while the remaining 10 studies did not report a significant association. Eighteen out of 27 studies (80%) had a short follow-up period of 1 year or less. Among the five high-quality studies that met all the domains of the quality assessment criteria, four showed a positive association. Conclusion The variation in results could relate to the quality of the studies, follow-up period, anticholinergic risk assessment tool used and the study setting. Sixty-three percent (n = 17) of all the included studies, but almost all of the high-quality studies with an extended follow-up, reported a positive correlation between anticholinergic burden and mortality. Further high-quality research, using standardized measures and with adequate follow-up periods, is required to confirm the relationship between anticholinergic burden and mortality.