Objectives Approximately two‐thirds of patients undergoing cardiac surgery experience postoperative complications, which may lead to significant clinical consequences. RBT‐1, an investigational drug with anti‐inflammatory and antioxidant properties, elicits a preconditioning response and was shown to improve clinical outcomes when administered within 24–48 hours prior to surgery (modified intention‐to‐treat population). The current post hoc analysis evaluated the efficacy of RBT‐1 in reducing postoperative complications in the entire study population without excluding patients based on when surgery occurred relative to study drug administration. Methods A total of 135 patients were randomized to receive a single infusion of RBT‐1 ( n = 91) or placebo ( n = 44) at least 1 day before undergoing nonemergent coronary artery bypass graft (CABG) and/or heart valve surgery on cardiopulmonary bypass (CPB) and were followed for 90 days postsurgery. Clinical outcomes assessed included ventilator time, intensive care unit (ICU) and hospital length of stay (LOS), cardiopulmonary readmission, and other clinical events of interest. Results In this analysis, RBT‐1 reduced ventilator time, ICU, and hospital LOS by 0.98 days (NS), 2.59 days ( p = 0.026), and 1.35 days (NS), respectively, compared with placebo. The incidence of 30‐day cardiopulmonary readmission was significantly reduced by RBT‐1 (4.6% vs. 17.5%, placebo; p = 0.035). Additionally, RBT‐1 showed a trend in reductions in several clinical events of interest, including anemia, atrial fibrillation, and fluid overload. Conclusions Trends in improved clinical outcomes were seen with RBT‐1 treatment in this post hoc analysis that included all patients enrolled in a Phase 2 clinical study regardless of surgery delay beyond 2 days posttreatment. A Phase 3 study is underway to confirm these improved clinical outcomes in a larger study population. Trial Registration: ClinicalTrials.gov identifier: NCT06021457