The integration of regional anesthesia (RA) with general anesthesia (GA) has become a central component of multimodal strategies to improve perioperative pain management. This approach not only enhances analgesic efficacy but also reduces opioid requirements and mitigates opioid-related adverse effects. By targeting peripheral or neuraxial nociceptive pathways, RA attenuates the surgical stress response and decreases central sensitization, complementing the systemic actions of GA. The combined application of RA and GA has shown substantial benefits across a wide range of surgical procedures, including abdominal, thoracic, orthopedic, and pediatric operations. Reported advantages include improved hemodynamic stability, enhanced pulmonary function, earlier ambulation, faster gastrointestinal recovery, and greater patient satisfaction. Moreover, recent evidence indicates a positive association between effective postoperative pain control and long-term outcomes, such as reduced incidence of persistent postsurgical pain, better functional independence, and even improved immune function and survival following cancer surgery. The development of sustained-release local anesthetic delivery systems, which provide localized and prolonged analgesia, further extends the benefits of RA-GA integration into the postoperative period. This review summarizes the mechanistic rationale, clinical applications, and future directions of RA-GA combinations in modern surgical care, with special emphasis on their role in enhanced recovery after surgery protocols.