Extracorporeal life support (ECLS) components designed to reduce clot formation have been developed, but thrombosis remains a significant challenge, requiring systemic anticoagulation. To address this, we evaluated a nitric oxide (NO) releasing extracorporeal circuit (ECC) in a 5 day ovine venovenous ECLS model without systemic anticoagulation. Fifteen sheep, weighing 40–52 kg, were instrumented and assigned to three groups (n = 5 each): 1) Control— “naïve” ECC without anticoagulation; 2) Sham—CarboSil-coated ECC; and 3) NOSA—NO-releasing ECC+100 ppm NO in the sweep gas. Animals were monitored until meeting two of the three end-point criteria defined by device resistance five times baseline, greater than 50% decrease in blood flow after RPM adjustments, or post-oxygenator SO₂ less than 95%. Extracorporeal Life Support flow was adjusted from 1 L/min (0–24 h), 0.75 L/min (25–48 h) to 0.5 L/min (49 h to study end). Data collected included hemodynamics, ECC performance, coagulation markers, cellular activity, and NO toxicity. The NO-releasing ECC prolonged survival to ~120 h with lower resistance and plasma-free hemoglobin, stable coagulation, and final MetHb levels less than 5%. Activated clotting times (ACTs) were less than 200 s in all groups. These findings suggest that NO-releasing ECCs in a highly translational preclinical ovine model may improve ECLS safety while reducing reliance on systemic anticoagulation.