Refractory hypoxemia (RH) during venovenous extracorporeal membrane oxygenation (VV ECMO) support is a complex problem that limits the benefit of this therapy. The need for sustained deep sedation and delays in active rehabilitation are considered as a direct consequence of RH. Changing from VV ECMO to a configuration that returns the flow to pulmonary artery, such as venopulmonary extracorporeal membrane oxygenation (VPa ECMO) may decrease recirculation and improve systemic oxygen delivery. We present a retrospective report that describes the impact of VPa ECMO on oxygenation during sedation withdrawal in 41 patients who received VV ECMO for coronavirus disease 2019 (COVID-19). We evidenced that arterial oxygen pressure (PaO₂) increased from 68 to 112.3 mm Hg (p = 0.001) with a reduction of ECMO flow (5.7–4.8 L/m; p = 0.001). Other findings included lower rates of depth sedation (Richmond Agitation Sedation Scale [RASS] ≤3, 37–63%; p = 0.007) and lower requirement inotropic support assessed by LVIS score (4.7–1.1; p = 0.005). Discharge survival was 54% with a sustained benefit until day 79. This cannulation strategy improved effectively PaO₂ in this cohort, it may be an alternative in patients with RH in VV ECMO.