Cardiothoracic surgery is associated with significant trauma, making effective postoperative pain management critical for enhanced recovery. Traditional regional analgesia is often limited by the short duration of single-dose local anesthetics or complications associated with continuous catheter techniques, which can hinder effective pain control during the intense 24–72-hour postoperative period. Liposomal bupivacaine (LB), a multivesicular liposome formulation of bupivacaine, provides a single-dose analgesic effect lasting up to 72 hours. This extended-release profile offers a novel, catheter-free approach to regional analgesia, with the potential to reduce catheter-related complications and serve as a key component of multimodal analgesia. This review systematically summarizes the pharmacological mechanisms and clinical applications of LB in cardiothoracic surgery. The evidence indicates that LB enables prolonged analgesia with a single dose, may reduce perioperative opioid consumption, and facilitates early recovery of respiratory function by avoiding interference with anticoagulation and mobilization. We critically evaluate ongoing controversies, including its comparative analgesic efficacy against established techniques like thoracic epidural analgesia, limitations due to its physical properties affecting tissue spread, and challenges related to its cost-effectiveness in different healthcare systems. This review aims to provide a comprehensive reference for optimizing multimodal analgesia protocols with LB in cardiothoracic surgery.