Breast surgeons need to deliver optimal pain relief to patients following breast surgeries. The purpose of this study was to assess the analgesic efficacy of ketamine and dexamethasone (DEX) when combined with bupivacaine in ultrasound-guided serratus anterior plane block (US-guided SAPB) for simplified radical mastectomy (MRM) procedures. Methods: This randomized, double-blind trial was conducted on 60 females between 20 and 60 years old with an American Society of Anesthesiologists (ASA) physical status classification of I to III undergoing MRM. Participants were randomly assigned to one of two equal groups that received US-guided SAPB with a solution of bupivacaine 0.25% and 4 mg of DEX in group A and plus 50 mg ketamine in group B. Results: Group B exhibited a significant reduction in pain score, total morphine consumption throughout the initial twenty-four hours following the procedure, and patients requiring morphine compared to group A. Group B exhibited a significant reduction in hemodynamic measurements compared to group A. Group B exhibited a significantly delayed time to the first analgesic request compared to group A. Conclusions: For patients undergoing MRM under general anesthesia, adding ketamine and DEX to bupivacaine enhances the US-guided SAPB analgesia with stable hemodynamics and minor adverse effects