Background Sodium-glucose co-transporter (SGLT) inhibitors reduce cardiovascular outcomes including mortality in several populations; however, their effect on atrial fibrillation/flutter (AF) remains unclear. Our objective was to determine whether SGLT inhibitors reduce AF and whether a history of AF modifies the effect of SGLT inhibitors on the composite of heart failure hospitalization or cardiovascular death. Methods and Results We searched MEDLINE, Embase, and CENTRAL to March 2021. Pairs of reviewers identified randomized controlled trials that compared an SGLT inhibitor with placebo or no therapy. We pooled data using RevMan 5.4.1, assessed risk of bias using the Cochrane tool, and determined the overall quality of evidence using Grades of Recommendation, Assessment, Development and Evaluation. Thirty-one eligible trials reported on AF events (75 279 participants, mean age 62 years, 35.0% women). Moderate quality evidence supported a lower risk of serious AF events with SGLT inhibitors (1.1% versus 1.5%; risk ratio 0.75 [95% CI, 0.66-0.86]; I=0%). A similar reduction in total AF events was also noted with SGLT inhibitors. Three trials reported on heart failure hospitalization/cardiovascular death stratified by a baseline history of AF (18 832 participants, mean age 66 years, 38.1% women); in patients with a history of AF, SGLT inhibitors resulted in a lower risk in the composite of heart failure hospitalization or cardiovascular death (hazard ratio, 0.70 [95% CI, 0.57-0.85]; I=0%)-similar to the effect estimate for patients without AF, value for interaction: 1.00. Conclusions SGLT inhibitors may reduce AF events and likely reduce heart failure hospitalization/cardiovascular death to a similar extent in patients with and without AF.