Veno-arterial extracorporeal membrane oxygenation (V‑A ECMO) is a critical care therapy for patients with severe cardiorespiratory failure, and it is associated with high in‑hospital mortality rates. Causes are the complex device-patient interaction and the choice of individual ECMO circuit components: oxygenator, pump, and cannulas. To evaluate the impact of cannulas sizes and pump selection on device-induced hemolysis, circuit operation conditions and patient hemodynamics, an in silico clinical trial combining lumped parameter modeling, computational fluid dynamics, laboratory, and clinical data, was performed. Two cannula configurations (small: 19 Fr and 15 Fr, large: 29 Fr and 23 Fr) alongside three pumps (Rotaflow, DP3, and Revolution) were tested each on a virtual patient cohort consisting of 30 V‑A ECMO patients. Small cannulas led to increased circuit resistances requiring higher pump speeds and yielding elevated hemolysis levels when compared to large cannulas. The pumps had hemolytic risks, however appropriate cannula selection enabled comparable blood damage potential across all pumps. No noticeable differences in patient hemodynamics were observed between the two cannula configurations. Our findings highlight the importance of cannula selection on ECMO performance. Low circuit resistance was revealed to be a crucial factor for a hemoprotective ECMO therapy.