Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) and TRAIL-receptor-2 (TRAIL-R2) are associated with atherosclerosis. This meta-analysis aimed to investigate the potential association between TRAIL/TRAIL-R2 with mortality or cardiovascular (CV) events. PubMed, Embase, and Cochrane Library were searched for reports published up to May 2021. Reports were included when the association between TRAIL or TRAIL-R2 and mortality or CV events was reported. Considering the heterogeneity between studies, we used the random-effects model for all analyses. Ultimately, the meta-analysis included 18 studies (16,295 patients). The average follow-up ranged from 0.25 to 10 years. Decreased TRAIL levels were negatively associated with all-cause mortality [rank variable, hazard ratio (HR), 95% CI, 2.93, 1.94–4.42; I2 = 0.0%, Pheterogeneity = 0.835]. Increased TRAIL-R2 levels were positively associated with all-cause mortality (continuous variable, HR, 95% CI, 1.43, 1.23–1.65; I2 = 0.0%, Pheterogeneity = 0.548; rank variable, HR, 95% CI, 7.08, 2.70–18.56; I2 = 46.5%, Pheterogeneity = 0.154), CV mortality (continuous variable, HR, 95% CI, 1.33, 1.14–1.57; I2 = 0.0%, Pheterogeneity = 0.435), myocardial infarction (continuous variable, HR, 95% CI, 1.23, 1.02–1.49; rank variable, HR, 95% CI, 1.49, 1.26–1.76; I2 = 0.7%, Pheterogeneity = 0.402), and new-onset heart failure (rank variable, HR, 95% CI, 3.23, 1.32–7.87; I2 = 83.0%, Pheterogeneity = 0.003). In conclusion, decreased TRAIL was negatively associated with all-cause mortality, and increased TRAIL-R2 was positively associated with all-cause mortality, CV mortality, myocardial infarction, and heart failure.