Background: Regional anesthesia techniques constitute an important part of successful analgesia strategies in the perioperative care of patients undergoing breast surgery. The advent of ultrasound-guided regional anesthesia has led to the development of fascial plane blocks. The large array of blocks available for postoperative analgesia in breast surgery has increased the accessibility of regional anesthesia but has also created a dilemma of choice. This study compared the analgesic efficacy of the ultrasound-guided modified pectoral nerve (PECS) block and erector spinae plane block (ESPB) in patients undergoing radical mastectomy. Methods: Seventy women were enrolled in this prospective, double-blind, randomized control trial. After exclusion, 67 female patients who underwent radical mastectomy were finally analyzed. Ultrasound-guided PECS blocks and ESPBs were performed with 30 ml 0.25% bupivacaine. Postoperative morphine and pain scores were compared between the groups. Results: Postoperative total morphine consumption in the first 24 h was significantly higher in the PECS group (P < 0.001). The ESPB group exhibited significantly reduced morphine consumption at all postoperative time points. Numeric rating scale scores were lower in the ESPB group at 6, 12, and 24 h postoperatively at rest and when coughing. Conclusions Ultrasound-guided bi-level ESPBs provided better postoperative analgesia than PECS blocks after radical mastectomy surgery.