Introduction: Higher intraoperative opioid doses may be associated with worse long-term oncological outcomes after radical prostatectomy (RP) for prostate cancer. We aimed to evaluate the impact of higher doses of intraoperative opioids and type of anesthesia on biochemical recurrence (BCR) and mortality after RP in a high-volume tertiary center. Methods: All patients underwent RP at our center between 2015 and 2021. The role of major intraoperative opioid agents, such as sufentanil remifentanil, and morphine milligram equivalents (MMEs), as well as the type of anesthesia [total intravenous anesthesia (TIVA), versus a combination of TIVA and epidural anesthesia, versus solely epidural anesthesia], was assessed in predicting BCR and survival after RP. Results: A total of 1137 patients who had a median age of 66 years (interquartile range: 61–72) were included. Overall, 1062 (93%) patients received TIVA, 37 (3%) received TIVA and epidural anesthesia, and 41 (4%) only epidural anesthesia. At a median follow-up of 431 days (interquartile range: 381–639) from RP, 257 (24%) patients developed a BCR. Accordingly, at a median follow-up of 500 days (interquartile range: 450–750), 33 (2.9%) patients died. The type of anesthesia, as well as the dosage or type of the selected intraoperative opioid agents, did not affect either BCR or long-term overall survival. Conclusions: These findings suggest that intraoperative opioid application during RP has no negative oncological impact in the short and long term in patients with localized prostate cancer. Accordingly, combined TIVA and epidural anesthesia, as well as solely epidural anesthesia were associated with similar short- and long-term outcomes compared to TIVA.