ABSTRACT Background Dyspnea is a critical component of chronic obstructive pulmonary disease (COPD). Ensifentrine, a novel PDE3/PDE4 inhibitor, was evaluated in the Phase 3 ENHANCE-1/2 clinical trials. Here, we report the effect of ensifentrine on dyspnea using pooled data from the ENHANCE trials. Methods The pooled population (ensifentrine, n = 975; placebo, n = 574) included patients aged 40–80 years with post-bronchodilator FEV1/FVC <0.7, FEV1 30–70% predicted, mMRC Dyspnea Scale score ≥ 2, and a smoking history ≥ 10 pack-years. Patients taking dual LAMA/LABA or LAMA/LABA/ICS triple therapy were excluded. Dyspnea measures included the Transition Dyspnea Index (TDI), Evaluating Respiratory Symptoms (E-RS), and rescue medication use. Results After 24 weeks, ensifentrine significantly improved TDI scores (least-squares mean difference, 0.97; 95% CI, 0.64, 1.30; p < 0.001) and across all TDI subdomains. Ensifentrine-treated patients were more likely to be TDI responders at week 24 (p < 0.001), which was consistent across clinically-relevant subgroups. Ensifentrine-treated patients had improved E-RS breathlessness subdomain scores (p = 0.053) and reduced rescue medication use (p = 0.002). The most common adverse reactions were back pain (ensifentrine, 1.8% vs placebo, 1.0%), hypertension (1.7% vs 0.9%), urinary tract infection (1.3% vs 1.0%), diarrhea (1.0% vs 0.7%). Conclusion Ensifentrine produced clinically meaningful improvements in multiple dyspnea measures in patients with symptomatic, moderate-to-severe COPD. A limitation of this study was the exclusion of patients taking dual LAMA/LABA and LAMA/LABA/ICS triple therapy. Clinical trial registration www.clinicaltrials.gov identifiers are ENHANCE-1: NCT04535986; ENHANCE-2: NCT04542057.