Cardiopulmonary bypass (CPB) produces inflammation and oxidative stress, which contribute to postoperative complications after cardiac surgery. F₂-Isoprostanes (F₂-IsoPs) are products of lipid oxidative injury and represent the most accurate markers of oxidative stress. In adults undergoing cardiac surgery, CPB is associated with elevated IsoPs. The relationship between F₂-IsoPs and perioperative end-organ function in infants with single-ventricle physiology, however, has not been well studied. This study prospectively enrolled 20 infants (ages 3–12 months) with univentricular physiology undergoing elective stage 2 palliation (bidirectional cavopulmonary anastomosis). Blood samples were collected before the surgical incision (T0), 30 min after initiation of CPB (T1), immediately after separation from CPB (T2), and 24 h postoperatively (T3). Plasma F₂-IsoP levels were measured at each time point and correlated with indices of pulmonary function and other relevant clinical variables. Plasma F₂-IsoPs increased significantly during surgery, with highest levels seen immediately after separation from CPB (p < 0.001). After separation from CPB, increased F₂-IsoP was associated with lower arterial pH (ρ = −0.564; p = 0.012), higher partial pressure of carbon dioxide (PaCO₂; ρ = 0.633; p = 0.004), and decreased lung compliance (ρ = –0.783; p ≤ 0.001). After CPB, F₂-IsoPs did not correlate with duration of CPB, arterial lactate, or immediate postoperative outcomes. In infants with single-ventricle physiology, CPB produces oxidative stress, as quantified by elevated F₂-IsoP levels. Increased F₂-IsoP levels correlated with impaired ventilation in the postoperative period. The extent to which F₂-IsoPs and other bioactive products of lipid oxidative injury might predict or contribute to organ-specific stress warrants further investigation.