Background: Acute pain after surgery can increase the likelihood of developing persistent pain, which is why effective analgesia techniques and pain medications are crucial during the perioperative period. Uncontrolled acute pain following surgery can lead to impaired functional recovery, increased opioid use, and prolonged treatment durations. The Erector Spinae Plane Block (ESPB) is a technique commonly used for managing pain in thoracic surgeries. This study aimed to assess the impact of ultrasound-guided ESPB on pain scores, opioid consumption, and the inflammatory stress response of surgical wounds, as indicated by the neutrophil-to lymphocyte ratio (NLR) after modified radical mastectomy (MRM) surgery. Patients and Methods: Twenty-eight female patients (18–60 years) undergoing MRM were randomly divided into two groups of 14 each. One group received general anesthesia and an ESPB with 0.4 mL/kg BW of 0.125% levobupivacaine, while the other group received the control treatment. Results: The results showed that the NRS was significantly lower in the ESPB group up to 24 hours postoperatively (p < 0.050). The p-values for the NLR at 12 hours (p = 0.007) and 24 hours (p = 0.001) after surgery were also significant. The NLR in the ESPB group was more stable. Opioid consumption was reduced by 63.26% in the ESPB group. The length of stay (LOS) in the hospital was shorter for the ESPB group (p = 0.019). Conclusion: General anesthesia (GA) combined with ESPB in patients undergoing unilateral MRM surgery resulted in lower NRS and NLR scores, reduced opioid consumption, and a shorter hospital LOS.