Background: Postoperative delirium (POD) following surgery is a prevalent and distressing condition associated with adverse patient outcomes and an increased healthcare burden. Objectives: To assess the effectiveness of the Safe Brain Initiative care bundle (SBI-CB) in reducing POD in the postanesthesia care unit (PACU). Design: A multicenter, quality-improvement initiative with retrospective analysis of collected data. Setting: The study was conducted in the operating rooms and postanesthesia care units (PACUs) of four hospitals across Denmark and Turkey. Patients: The convenience sample of patients were aged ≥18 years, scheduled for surgery, and could communicate verbally. Age, sex, preoperative delirium, and the American Society for Anesthesiology physical status classification were used in statistical methods to control for potential confounding influences. Intervention: The SBI-CB, 18 delirium-reducing recommendations aligned with international guidelines. The intervention included patient education, staff training, coordination meetings across centers, and a dashboard for the monitoring of outcomes in the PACU. Main outcome measures: The primary outcome was the POD trend in the PACU during implementation months, assessed through Nu-DESC screening at up to three time points in the PACU. We also examined the length of hospital stay. Results: Data were collected from 18,697 adult patients across four hospitals. Initial POD incidence in the PACU after the first three months was 16.36% across all sites (n = 1021). POD in the PACU was observed across all age groups, with peak incidence in younger (18–35 years) and older (>75 years) patients. General anesthesia and longer surgical duration (>1 h) were identified as significant risk factors for POD in the PACU. Matched patients who experienced POD in the PACU had longer stays in hospital, with a mean increase from 35 to 69 h (p < 0.001). Implementation of the SBI-CB was associated with a decreased risk of POD in the PACU for each month of SBI-CB implementation (adjusted odds ratio 0.96, 95% confidence interval: [0.94, 0.97], p < 0.001). Conclusions: The presented pragmatic implementation of a multidisciplinary care bundle, encompassing pre-, intra-, and postoperative measures alongside outcome monitoring, has the potential to significantly reduce the incidence of POD in the PACU. Improved patient outcomes may be achieved for general surgical departments with patient cohorts not typically considered at risk for developing POD. Trial Registration: Clinicaltrials.gov, identifier NCT05765162.