Introduction: In response to a perceived high incidence of acute kidney injury following cardiopulmonary bypass at our institution, a quality improvement initiative consisting of a systematic change to a delivered oxygen (DO2) goal-directed perfusion practice was implemented. We sought to maintain DO2 > 270 mL/min/m2 to reduce the incidence of acute kidney injury. Methods: ’The study population included all patients receiving isolated, non-emergent, on-pump coronary artery bypass grafting from January 2015 through December 2018, excluding patients requiring preoperative hemodialysis. DO2 goal-directed perfusion was instituted in February 2017. Acute kidney injury was defined using Acute Kidney Injury Network criteria. Results: The pre–goal-directed perfusion cohort included 257 patients, and the post–goal-directed perfusion cohort included 226 patients. The DO2 was significantly higher in the post–goal-directed perfusion group (p < 0.001). Postoperative change in serum creatinine and incidence of acute kidney injury were significantly lower in the post–goal-directed perfusion group (p < 0.001, p = 0.001, respectively). Estimation with probit and ordered probit models support these findings. Conclusion: This initiative confirms previous assertions that DO2 is a critical intraoperative parameter and should direct perfusion intervention accordingly.