<jats:sec><jats:title>Objective</jats:title><jats:p> The aim of this study was to conduct a systematic review and meta-analysis to investigate the impact of premorbid beta-blockers on mortality in patients with sepsis. </jats:p></jats:sec><jats:sec><jats:title>Data Sources</jats:title><jats:p> We searched EMBASE, the Cochrane Central Register of Controlled Trials, and MEDLINE for eligible studies. The protocol was registered at the PROSPERO (CRD42021256813). </jats:p></jats:sec><jats:sec><jats:title>Study Selection</jats:title><jats:p> Two authors independently evaluated the following inclusion criteria: (1) randomized controlled trials, cohort studies, cross-sectional studies; (2) patients with sepsis aged ≥18 years, and (3) premorbid beta-blocker use. </jats:p></jats:sec><jats:sec><jats:title>Data Extraction</jats:title><jats:p> Two authors extracted the patients’ characteristics and outcomes independently. All analyses were performed using the random-effects models. The primary outcome was short-term mortality, defined as mortality within 30 days, in-hospital or intensive care unit mortality. </jats:p></jats:sec><jats:sec><jats:title>Data Synthesis</jats:title><jats:p> Ten studies (n = 24 748 patients) were included. The pooled odds ratio (OR) of short-term mortality associated with the premorbid use of beta-blockers was 0.85 (95% confidence interval [CI], 0.69-1.04; P = .12; I<jats:sup>2</jats:sup> = 50%). Five studies reported an adjusted OR of short-term mortality. The pooled adjusted OR of short-term mortality associated with the premorbid use of beta-blockers was 0.73 (95% CI, 0.65-0.83; P &lt; .001; I<jats:sup>2</jats:sup> = 0%). </jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p> Premorbid beta-blockers were associated with a lower short-term mortality in patients with sepsis. </jats:p></jats:sec>