Objectives: EuroSCORE II is widely used to predict perioperative and 30-day mortality in cardiac surgery, yet data on its ability to predict long-term outcomes remain limited. This study investigates whether EuroSCORE II is associated with one-year and long-term mortality in a heterogeneous population undergoing major cardiac surgery with cardiopulmonary bypass. Methods: A retrospective cohort study was conducted including 2179 patients who underwent elective or urgent cardiac surgery with cardiopulmonary bypass between 2017 and 2021 at the University Hospital Salzburg. Data were extracted from the Salzburg Intensive Care database (SICdb) and supplemented with mortality information from Statistik Austria. EuroSCORE II values were compared between survivors and non-survivors. Kaplan–Meier analyses, Cox regression and logistic regression with ROC analysis were performed to evaluate the predictive association of EuroSCORE II with mortality. Results: EuroSCORE II was significantly higher in patients who died within one year and in those who died during a mean follow-up period of 1152.67 ± 521.39 days. Patients who survived at least one year had a median EuroSCORE II of 2.2, whereas those who died within one year had a median of 7.0. Cox regression demonstrated a hazard ratio of 1.062 for one-year mortality and 1.058 for long-term mortality. Kaplan–Meier curves showed significantly reduced survival with increasing EuroSCORE II quartiles. Logistic regression for one-year mortality yielded an AUC of 0.773, indicating good discriminative ability. Conclusions: EuroSCORE II is significantly associated with long-term mortality after major cardiac surgery, demonstrating good discriminatory performance. These findings support its potential utility not only as a short-term but also as a long-term prognostic indicator in cardiac surgery populations.