Background <p>Despite ongoing efforts, the prescription of opioids is still common. Long-term opioid use has been associated with an increased risk of adverse cardiovascular outcomes.</p> Objective <p>We aimed to evaluate the association between opioid use and the risk of new-onset atrial fibrillation.</p> Methods <p>We performed a systematic review and meta-analysis of studies retrieved from MEDLINE and EMBASE databases according to PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines from inception to 29 January, 2024. The protocol was registered at PROSPERO (CRD42024512500). Two authors independently screened and extracted data from included studies. The quantitative analysis included only observational studies and results were synthesised by a pooled hazard ratio. Risk of bias was performed according to the ROBINS-I Cochrane tool, and the summary of evidence according to GRADE (Grading of Recommendations, Assessment, Development and Evaluations).</p> Results <p>Four out of 782 studies met the inclusion criteria for a quantitative analysis with 24,006,367 participants. Overall, 153,734 were opioid users. The proportion of women ranged from 13.2 to 100% and the median age ranged from 34 to 65 years. Studies reported 991,263 cases of new-onset atrial fibrillation. The pooled analysis showed a significant association between use of opioids and new-onset atrial fibrillation (hazard ratio 1.96, 95% confidence interval 1.43–2.69 with high heterogeneity). A sensitivity analysis by removing the study with the largest cohort showed similar results to the main analysis. In the summary of findings, the certainty of the evidence according to GRADE was moderate.</p> Conclusions <p>We found a significant association between opioid use and the risk of new-onset atrial fibrillation. When prescribing opioids, the risk of new-onset atrial fibrillation should be considered, especially in the presence of other risk factors for atrial fibrillation.</p>