When used as a driving gas during NIV in hypercapnic COPD exacerbation, a helium–oxygen (He/O ₂ ) mixture reduces the work of breathing and gas trapping. The potential for He/O ₂ to reduce the rate of NIV failure leading to intubation and invasive mechanical ventilation has been evaluated in several RCTs. The goal of this meta-analysis is to assess the effect of NIV driven by He/O ₂ compared to air/O ₂ on patient-centered outcomes in hypercapnic COPD exacerbation. Relevant RCTs were searched using standard procedures. The main endpoint was the rate of NIV failure. The effect size was computed by a fixed-effect model, and estimated as odds ratio (OR) with 95% confidence interval (CI). Additional endpoints were ICU mortality, NIV-related side effects, and the length and costs of ICU stay. Three RCTs fulfilled the selection criteria and enrolled a total of 772 patients (386 patients received He/O ₂ and 386 received air/O ₂ ). Pooled analysis showed no difference in the rate of NIV failure when using He/O ₂ mixture compared to air/O ₂ : 17 vs 19.7%, respectively; OR 0.84, 95% CI 0.58–1.22; p = 0.36; I ² for heterogeneity = 0%, and no publication bias. ICU mortality was also not different: OR 0.8, 95% CI 0.45–1.4; p = 0.43; I ²  = 5%. However, He/O ₂ was associated with less NIV-related adverse events (OR 0.56, 95% CI 0.4–0.8, p = 0.001), and a shorter length of ICU stay (difference in means = −1.07 day, 95% CI −2.14 to −0.004, p = 0.049). Total hospital costs entailed by hospital stay and NIV gas were not different: difference in means = −279$, 95% CI −2052–1493, p = 0.76. Compared to air/O ₂ , He/O ₂ does not reduce the rate of NIV failure in hypercapnic COPD exacerbation. It is, however, associated with a lower incidence of NIV-related adverse events and a shortening of ICU length of stay with no increase in hospital costs.