A critical factor in thrombus formation during venoarterial extracorporeal membrane oxygenation (VA ECMO) is prothrombotic flow dynamics generated by the drainage cannula’s design. This study aimed to create and evaluate a novel drainage cannula design which optimized blood flow dynamics to reduce thrombus formation. Computational fluid dynamics (CFD) was used to iteratively vary drainage cannula design parameters such as inner wall shape and side hole shape. The final novel design was then placed in an ex vivo blood circulation loop, and compared against a Bio-Medicus cannula (n = 6, each). Clot volume, hemolysis, and other parameters were measured to assess thrombus formation markers. The novel design consisted of a parabolic inner wall profile with closely spaced side holes angled at 30º to align with flow. When tested in the ex vivo loop, the novel design resulted in lower instances (two vs. four) and volumes of clot in the cannula (360.5 ± 254.8 vs. 1258.0 ± 651.7 µl) when compared to the Bio-Medicus cannula. Results from tests assessing hemolysis, platelet activation, and other thrombotic markers revealed a noninferior relationship between the novel and Bio-Medicus designs. Future work will explore the clinical applicability of these findings.