: The erector spinae plane block (ESPB) is a multimodal opioid-sparing component, providing chest-wall analgesia of variable extent, duration, and intensity. The objective was to examine the ESPB effect on perioperative opioid usage and postoperative rehabilitation when used within a Nociception Level (NOL) index-directed anesthetic protocol. : This prospective, randomized, controlled, open-label study was performed in adult patients undergoing on-pump cardiac surgery in a single tertiary hospital. Eighty-three adult patients who met eligibility criteria were randomly allocated to group 1 (Control, n = 43) and group 2 (ESPB, n = 40) and received general anesthesia with NOL index-directed fentanyl dosing. Preoperatively, group 2 also received bilateral single-shot ultrasound-guided ESPB (1.5 mg/kg/side 0.5% ropivacaine mixed with dexamethasone 8 mg/20 mL). Postoperatively, both groups received intravenous paracetamol (1 g every 6 h). Morphine (0.03 mg/kg) was administered for numeric rating scale (NRS) scores ≥4. : The median (IQR, 25th-75th percentiles) intraoperative fentanyl and 48 h morphine dose in group 2-to-group 1 were 1.2 (1.1-1.5) vs. 4.5 (3.8-5.5) µg·kg·h ( < 0.001) and 22.1 (0-40.4) vs. 60.6 (40-95.7) µg/kg ( < 0.001). The median (IQR) time to extubation in group 2-to-group 1 was 90 (60-105) vs. 360 (285-510) min ( < 0.001). Two hours after ICU admission, 87.5% of ESPB patients were extubated compared to 0% of controls ( < 0.001), and 87.5% were weaned off norepinephrine compared to 46.5% of controls ( < 0.001). The median NRS scores at 0, 6, 12, 24, and 48 h after extubation were significantly decreased in group 2. There was no difference in opioid-related adverse events and length of stay. : NOL index-directed ESPB reduced intraoperative fentanyl by 73.3% and 48 h morphine by 63.5%. It also hastened the extubation and liberation from vasopressor support and improved postoperative analgesia.