Background Awareness has recently risen about the potential associated risks to the cardiovascular health of cannabis users. The objective was to evaluate the possible association between major adverse cardiovascular events (MACE) and the use of cannabis or cannabinoids. Methods Original pharmacoepidemiological studies providing risk estimates on cannabis-related MACE (ie, cardiovascular death, non-fatal acute coronary syndrome (ACS) including myocardial infarction (MI) or non-fatal stroke) published from 1 January 2016 to 31 January 2023 were included in the systematic review exploring PubMed, Web of Science and Scopus (last search: 20 September 2023). Design, duration, baseline characteristics, exposure, inclusion criteria, sample size, effect size and confusing factors, including exposure to psychoactive substances, were extracted. Study quality was assessed using the ROBINS-E (risk of bias in non-randomised studies—of exposures) tool. In the meta-analysis, adjusted effect estimates and their 95% CIs were pooled using a DerSimonian and Laird random effect model with inverse variance weighting based on the type of outcome (PROSPERO: CRD42023401401). Results Overall, 24 articles were included from 3012 initial records, including 17 cross-sectional studies, 6 cohort studies and 1 case-control study. Exposure corresponded to the use of cannabis in all studies, with one focused on medical cannabis. The estimated risk ratio (RR) was 1.29 (95% CI 1.05 to 1.59) for ACS, 1.20 (1.13 to 1.26) for stroke and 2.10 (1.29 to 3.42) for cardiovascular death. As measured in two studies, no statistically significant association was found for the composite outcome combining ACS and stroke. The focused analysis restricted to cohort studies yielded comparable results to the primary model (RR=1.32, 1.01 to 1.73). Conclusions This systematic review and meta-analysis uses an original approach centred on real-world data. The findings reveal positive associations between cannabis use and MACE. These findings should encourage investigating cannabis use in all patients presenting with serious cardiovascular disorders. PROSPERO registration number CRD42023401401. No data are available. The data explored in this systematic review and meta-analysis have been extracted from publicly available databases. Although the authors will not share the data directly, any interested researcher may apply the search strategy developed for this analysis, available in the online supplemental appendix.