Background: Thrombosis within extracorporeal membrane oxygenation (ECMO) circuits is a common complication that dominates clinical management of patients receiving mechanical circulatory support. Prior studies have identified that over 80% of circuit thrombosis can be attributed to tubing-connector junctions. Methods: A novel connector was designed that reduces local regions of flow stagnation at the tubing-connector junction to eliminate a primary source of ECMO circuit thrombi. To compare clotting between the novel connectors and the traditional connectors, both in vitro loops and an in vivo caprine model of long-term (48 h) ECMO were used to generate tubing-connector junction clots. Results: In vitro, the traditional connectors uniformly (9/9) formed large thrombi, while novel connectors formed a small thrombus in only one of nine ( p < 0.0001). In the long-term goat ECMO circuits, the traditional connectors exhibited more thrombi ( p < 0.04), and these thrombi were more likely to protrude into the lumen of the tubing ( p < 0.001). Conclusion: Both in vitro and in vivo validation experiments successfully recreated circuit thrombosis and demonstrate that the adoption of novel connectors can reduce the burden of circuit thrombosis.