Abstract Background Mitigating or reducing the risk of medication harm is a global policy priority. But evidence reflecting preventable medication harm in medical care and the factors that derive this harm remain unknown. Therefore, we aimed to quantify the prevalence, severity and type of preventable medication harm across medical care settings. Methods We performed a systematic review and meta-analysis of observational studies to compare the prevalence of preventable medication harm. Searches were carried out in Medline, Cochrane library, CINAHL, Embase and PsycINFO from 2000 to 27 January 2020. Data extraction and critical appraisal was undertaken by two independent reviewers. Random-effects meta-analysis was employed followed by univariable and multivariable meta-regression. Heterogeneity was quantified using the I² statistic, and publication bias was evaluated. PROSPERO: CRD42020164156. Results Of the 7780 articles, 81 studies involving 285,687 patients were included. The pooled prevalence for preventable medication harm was 3% (95% confidence interval (CI) 2 to 4%, I² = 99%) and for overall medication harm was 9% (95% CI 7 to 11%, I² = 99.5%) of all patient incidence records. The highest rates of preventable medication harm were seen in elderly patient care settings (11%, 95% 7 to 15%, n = 7), intensive care (7%, 4 to 12%, n = 6), highly specialised or surgical care (6%, 3 to 11%, n = 13) and emergency medicine (5%, 2 to 12%, n = 12). The proportion of mild preventable medication harm was 39% (28 to 51%, n = 20, I² = 96.4%), moderate preventable harm 40% (31 to 49%, n = 22, I² = 93.6%) and clinically severe or life-threatening preventable harm 26% (15 to 37%, n = 28, I² = 97%). The source of the highest prevalence rates of preventable harm were at the prescribing (58%, 42 to 73%, n = 9, I² = 94%) and monitoring (47%, 21 to 73%, n = 8, I² = 99%) stages of medication use. Preventable harm was greatest in medicines affecting the ‘central nervous system’ and ‘cardiovascular system’. Conclusions This is the largest meta-analysis to assess preventable medication harm. We conclude that around one in 30 patients are exposed to preventable medication harm in medical care, and more than a quarter of this harm is considered severe or life-threatening. Our results support the World Health Organisation’s push for the detection and mitigation of medication-related harm as being a top priority, whilst highlighting other key potential targets for remedial intervention that should be a priority focus for future research.