Venopulmonary arterial (VPA) extracorporeal membrane oxygenation (ECMO) is emerging as an alternative to traditional venovenous (VV) ECMO for respiratory failure. This study compares rates of hemolysis and acute kidney injury (AKI) between VPA and VV ECMO. We retrospectively analyzed 142 patients (VPA: n = 84, VV: n = 58) who underwent ECMO from 2019 to 2023. Plasma-free hemoglobin (pfHb) was measured as a marker for hemolysis and AKI was assessed using daily creatinine levels. Mixed-effects linear regression and Cox proportional hazards models were used to assess associations between ECMO modality, hemolysis, and AKI. No significant differences in pfHb, creatinine, or AKI incidence were observed between VV and VPA ECMO (p > 0.05). Extracorporeal membrane oxygenation modality was not a significant predictor of pfHb levels (p = 0.376), creatinine levels (p = 0.337), or time to AKI (hazard ratio [HR] = 0.94, 95% confidence interval [CI] = 0.39–2.30; p = 0.898). Centrimag pumps were associated with lower pfHb compared with Cardiohelp (29% reduction, p = 0.002). Increased pump speed correlated with elevated pfHb (27% increase per 1,000 RPM, p = 0.003). Venopulmonary arterial and VV ECMO demonstrate similar hemolysis and AKI profiles. Pump type and speed significantly influence hemolysis, emphasizing the importance of optimal ECMO configuration and management in minimizing complications.