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Background and Aims Chronic post-mastectomy pain (CPMP) affects 20–50% of patients, with regional anesthesia increasingly used to mitigate acute and chronic pain. While both PECS II and ESP blocks are effective for acute analgesia, their long-term impact on CPMP remains understudied. This study aimed to compare the effects of preoperative PECS I-II and ESP blocks on acute pain control, opioid requirements, and CPMP incidence at 3 months.Methods In this prospective cohort study, 44 patients undergoing modified radical mastectomy under general anesthesia received either ultrasound-guided PECS I-II (n=21) or ESP blocks (n=23) with 0.25% bupivacaine. Primary outcomes included postoperative Numerical Rating Scale (NRS) scores, 24-hour morphine consumption, and CPMP incidence (NRS≥1 at 3 months). Secondary outcomes included neuropathic pain (DN4/DN2 scores) and quality of life (SF-12). Statistical analysis used SPSS v27.Results Both groups demonstrated comparable intraoperative fentanyl use (p=0.218) and 24-hour morphine consumption (4.8±1.9 vs. 4.3±2.0 mg, p=0.359). ESP provided longer time to first analgesia request (260±53 vs. 227±54 mins, p=0.048) and lower early NRS scores (p=0.016). At 3 months, CPMP incidence was similar (42.9% vs. 52.2%, p=0.537), with lymph node dissection (64% vs. 26%, p=0.013) and postoperative neuropathic pain (DN4≥4 at 24 h, p=0.042) identified as key risk factors. SF-12 physical scores were significantly lower in patients with CPMP (49.1±5.4 vs. 55.5±2.1, p<0.001).Conclusions PECS I-II and ESP blocks equivalently reduce acute postoperative pain, but neither significantly lowers CPMP incidence. Lymph node dissection and early neuropathic pain are critical risk factors for chronicity. While ESP prolongs analgesia duration, both techniques offer viable options for mastectomy pain management. Multimodal strategies targeting neuropathic pathways and surgical modifications for lymph node preservation warrant further exploration. This study provides actionable insights for optimizing regional anesthesia choices in breast surgery while highlighting unmet needs in chronic pain prevention.