Background: Chronic obstructive pulmonary disease (COPD) is a progressive lung disease marked by airway inflammation and obstruction. Ensifentrine is a novel inhaled PDE3 and PDE4 inhibitor with both bronchodilator and anti-inflammatory effects. Objectives: Comprehensively review the available evidence on ensifentrine and its potential role in COPD management. Design: Systematic review and meta-analysis with trial sequential analysis of randomized clinical trials. Data sources and methods: We systematically searched PubMed, Scopus, ScienceDirect, Cochrane Library, and Medline for clinical trials published between 2018 and August 2024 that evaluated the safety and efficacy of ensifentrine in patients with COPD. We assessed study quality using the RoB 2 tool and conducted the meta-analysis with the “meta” package in R (version 4.3.2), using the mean difference with a 95% confidence interval to evaluate changes in outcomes. Results: Five studies met the predefined inclusion criteria with 2519 participants. At week 12, the pooled analysis indicated that forced expiratory volume in 1 s (FEV ₁ ) and trough FEV ₁ were significantly increased in the ensifentrine group (mean difference (MD): 91.32; 95% CI: 69.63 to 113.01) and (MD: 40.90; 95% CI: 19.65 to 62.15), respectively. At week 24, the pooled analysis indicated that the evaluating respiratory symptoms total score was significantly decreased in the ensifentrine group (MD: −0.81; 95% CI: −1.36 to −0.27), transition dyspnea index score was significantly increased in the ensifentrine group (MD: 0.96; 95% CI: 0.62 to 1.29), no significant difference was observed in rescue medication use (MD: −0.30; 95% CI: −0.60 to 0.00), and no significant difference was observed in St. George’s Respiratory Questionnaire total score (MD: −1.46; 95% CI: −3.22 to 0.30). Based on subgroup analysis, higher doses were associated with more favorable results. Conclusion: In conclusion, owing to its dual effects, ensifentrine has a significant impact on improving pulmonary function and quality of life with minimal side effects. Promising results are expected if implied by synergizing with other drugs, however, more studies are needed to study the long-term effect on disease progression. Trial registration: The study protocol was published via PROSPERO: International Prospective Register of Systematic Reviews (#CRD42024570799).