Background Postoperative pain management after laparoscopic sleeve gastrectomy is still considered a major challenge. The current study was designed to assess if adding ketamine or dexmedetomidine to intraperitoneal bupivacaine could improve the quality and the duration of postoperative analgesia for morbidly obese patients undergoing laparoscopic sleeve gastrectomy. Methods Sixty patients scheduled for elective laparoscopic sleeve gastrectomy were randomly assigned to receive intraperitoneal instillation of bupivacaine (0.25 %) alone (group C), bupivacaine (0.25 %)/ketamine 0.5 mg/kg (group K) or bupivacaine (0.25 %)/dexmedetomidine 1µg/kg (group D) after sleeve gastrectomy. The primary outcome measured was the time to first postoperative rescue analgesia. Secondary outcomes included postoperative analgesic requirements, postoperative pain intensity measured by the Visual Analog Scale (VAS) and the incidence of shoulder pain. Results The time to first rescue analgesia was significantly longer (< 0.001) and the total amount of postoperative nalbuphine required was significantly lower in both the K and D groups (< 0.001) compared to the C group. Additionally, the time to first rescue analgesia was significantly longer in group D compared to group K. The VAS score was significantly lower in groups K and D compared to group C (P < 0.05) at most measuring points, with no significant difference between groups K and D. The incidence of postoperative shoulder pain was significantly higher in group C compared to groups K and D (< 0.001) with no statistically significant difference between groups K and D. Conclusion Adding either ketamine 0.5 mg/kg or dexmedetomidine 1µg/kg to intraperitoneal bupivacaine 0.25 % can safely improve postoperative analgesia resulting in a longer time to first rescue analgesia, lower VAS for pain values, reduced postoperative rescue analgesic requirements in the first postoperative 24 h and a lower incidence of postoperative shoulder pain.