While mechanical ventilation practices on venovenous extracorporeal membrane oxygenation (VV ECMO) are variable, most institutions utilize a lung rest strategy utilizing relatively low positive end-expiratory pressure (PEEP). The effect of PEEP titration using esophageal manometry during VV ECMO on pulmonary and cardiac function is unknown. This was a retrospective study of 69 patients initiated on VV ECMO between March 2020 through November 2021. Patients underwent standard PEEP (typically 10 cm H₂O) or optimal PEEP (PEEP titrated to an end-expiratory transpulmonary pressure 0–3 cm H₂O) throughout the ECMO run. The optimal PEEP strategy had higher levels of applied PEEP (17.9 vs. 10.8 cm H₂O on day 2 of ECMO), decreased incidence of hemodynamically significant RV dysfunction (4.55% vs. 44.0%, p = 0.0001), and higher survival to decannulation (72.7% vs. 44.0%, p = 0.022). Survival to discharge did not reach statistical significance (27% vs. 11%, p = 0.211). In univariate logistic regression analysis, optimal PEEP was associated with less hemodynamically significant RV dysfunction with an odds ratio (OR) of 0.06 (95% confidence interval [CI] = 0.01–0.27, p = 0.0008) and increased survival to decannulation with an OR of 3.39 (95% CI 1.23–9.79), p = 0.02), though other confounding factors may have contributed.