Purpose <p>Olezarsen has shown efficacy in hypertriglyceridemic and dyslipidemic populations of mixed cohorts, but its effectiveness in severe hypertriglyceridemia(SHTG) is unknown. This is a systematic review and meta-analysis to evaluate the efficacy of olezarsen in SHTG and the associated risk of pancreatitis.</p> Method <p>PubMed, Embase, and Cochrane databases were systematically searched for published trials comparing olezarsen vs placebo in SHTG patients up to December 03, 2025. We computed mean difference (MD) and risk ratio (RR) with 95%&#xa0;CI for continuous and binary endpoints, respectively, using a random-effects model. Significance level was set with P-value (&lt; 0.05).</p> Results <p>From 228 database records, three randomized trials involving 1127 patients were included, with a 12-month follow-up. Of these, 748 patients (66.3%) received olezarsen. Olezarsen significantly reduced the mean percentage change from baseline of triglyceride (TG) levels, especially for the non–familial chylomicronemia syndrome(non-FCS) population (MD =  − 59.95%; 95% CI − 76.00 to − 43.90; P = .001), of apolipoprotein C-III levels (MD =  − 66.68%; 95% CI − 80.86 to − 52.69; P = .0006) at 6&#xa0;months compared to placebo, albeit with significant heterogeneity. Significant reductions were also observed for other lipid parameters, specifically Non-high-density lipoprotein cholesterol (non-HDL-C) (MD = − 23.72%; 95% CI: − 27.35, − 20.09; P = .00001) and Remnant cholesterol(RC) (MD = − 55.30%;95% CI: − 62.05, -48.56; P = .00001) with an increase in LDL level. Olezarsen reduced the risk of acute pancreatitis (1.2% vs 8.7%; RR = 0.14; 95% CI: 0.07, 0.29; P = .00001) compared to placebo. No significant adverse events were observed between groups.</p> Conclusion <p>Our analysis suggests olezarsen may be an effective therapeutic option in SHTG for reducing lipids and acute pancreatitis risk. However, its long-term safety and efficacy remain to be explored in future trials in this cohort.</p>