The optimal therapy for submassive pulmonary embolism (sPE), defined by right ventricular dysfunction without hemodynamic instability, is uncertain. We conducted a systematic review and meta-analysis to compare the outcomes of catheter-directed thrombolysis (CDT) versus systemic anticoagulation (SA) alone in patients with sPE. We searched PubMed, EMBASE, Cochrane, ClinicalTrials.gov, and Google Scholar (from inception through May 2022) for studies comparing outcomes of CDT versus SA in sPE. Studies were identified, and data were extracted by 2 independent reviewers. We used a random-effects model to calculate risk ratios (RRs) with 95% confidence intervals (CIs). Outcomes included in-hospital, 30-day, 90-day, and 1-year mortality, major and minor bleeding, and need for blood transfusion. A total of 12 studies (1 randomized, 11 observational) with 9,789 patients were included. Compared with SA, CDT was associated with significantly lower in-hospital mortality (RR 0.41, 95% CI 0.30 to 0.56, p <0.00001), 30-day mortality (RR 0.37, 95% CI 0.18 to 0.73, p = 0.004), 90-day mortality (RR 0.36, 95% CI 0.17 to 0.72, p = 0.004), and a tendency toward lower 1-year mortality (RR 0.56, 95% CI 0.29 to 1.05, p = 0.07). The risks of major bleeding (RR 1.31, 95% CI 0.57 to 3.01, p = 0.53), minor bleeding (RR 1.67, 95% CI 0.77 to 3.63, p = 0.20), and the rates of blood transfusion (RR 0.34, 95% CI 0.10 to 1.15, p = 0.08) were similar between the 2 strategies. In conclusion, in patients with sPE, CDT is associated with significantly lower in-hospital, 30-day, and 90-day mortality and a tendency toward lower 1-year mortality with similar bleeding rates compared with SA. This study expands the evidence supporting CDT as first-line therapy for sPE, and randomized controlled trials are indicated to confirm our findings.