Patients with diabetes mellitus are at an increased risk of cardiovascular morbidity and all-cause mortality. Heart failure and type 2 diabetes often occur concomitantly, and each disease independently increases the risk for the other. Emerging data have revealed that some sodium-glucose cotransporter inhibitors (SGLTi) improve cardiovascular and renal outcomes, particularly in patients with type 2 diabetes. The magnitude of this effect in patients without any underlying condition remains unclear. As a result, we conducted a meta-analysis of the mortality outcomes of available SGLTi in patients with or without cardiovascular diseases, type 2 diabetes, cardiovascular risk factors, and heart failure. We performed a systematic review and meta-analysis of randomized, placebo-controlled major cardiovascular outcome trials of SGLTi in patients regardless of their cardiovascular disease or risk status. PubMed, Cochrane, Google Scholar, MEDLINE, and EMBASE were searched for the relevant studies. Three reviewers extracted study data and three reviewers summarized the strength of the evidence. Efficacy outcomes included all-cause mortality, major adverse cardiovascular events (myocardial infarction, stroke, or cardiovascular death), the composite of all-cause mortality, cardiovascular death, or hospitalization for heart failure. Odds ratios with 95% confidence intervals were pooled across trials to calculate the overall effect size. A total of 5043 all-cause mortality events were observed in the study groups. In 42,050 patients who received SGLTi, 2581 events were reported, and 2462 events were reported in 35,491 patients who received placebo (odds ratio = 0.86, 95% confidence interval 0.80-0.93, p = 0.0003). The use of SGLTi significantly reduced cardiovascular mortality compared with control across the patients' population (odds ratio = 0.86, 95% confidence interval 0.79-0.93, p = 0.0001). There was a consistent pattern of mortality beneficial estimates for all patients with different co-morbid conditions in the SGLTi-treated arm compared with the placebo-treated group. The presence or absence of significant cardiovascular disease risk factors (including a family history of premature coronary artery disease, baseline estimated glomerular filtration rate, dyslipidemia, hypertension, smoking, history of cardiovascular disease, and older age) did not affect the estimated mortality benefits. Sodium-glucose cotransporter inhibitors significantly reduced major adverse cardiovascular events, including hospitalization and all-cause mortality in patients with or without established atherosclerotic cardiovascular disease. We observed a beneficial trend in patients with heart failure with preserved ejection fraction, and no benefits in patients with stroke or myocardial infarction.