Postoperative pain control is recognized as a challenging surgical issue receiving high priority in the healthcare system, and opioids are routinely prescribed for anesthesia and pain relief. This study aimed to investigate the effects of ropivacaine administered intraperitoneally alone or combined with dexmedetomidine or fentanyl on postoperative pain control following laparoscopic cholecystectomy. This randomized double-blind clinical trial recruited three equal-size block-randomized groups of patients ( n = 138) scheduled for elective laparoscopic cholecystectomy at Valiasr Hospital, Arak, Iran, in 2019–2020 who received ropivacaine (40 mL/0.5%), ropivacaine (40 mL/0.5%) + dexmedetomidine (1 μg/kg), and ropivacaine (40 mL/0.5%) + fentanyl (1 μg/kg). No significant differences were observed among the three groups according to the vital signs (mean arterial pressure/heart-rate/oxygen saturation) in the study period and during surgery ( P > 0.05). Lower pain was revealed in the ropivacaine + dexmedetomidine group ( P = 0.001), with the lowest opioid dose in postoperative 24 hours ( P = 0.001). Moreover, no clinically significant differences were observed in complications among the three groups ( P = 0.483), and no patient developed ileus. Intraperitoneal ropivacaine administered with dexmedetomidine could relieve pain and reduce opioid use in postoperative 24 hours, without any complication and ileus. Therefore, intraperitoneal ropivacaine administered with dexmedetomidine is recommended for postoperative pain control in patients undergoing laparoscopic cholecystectomy. This study was approved by the Ethical Committee of Arak University of Medical Sciences (approval No. IR.ARAKMU.REC.1397.267) on December 30, 2018 and was registered in the Iranian Registry of Clinical Trials (No. IRCT 20141209020258N117) on July 13, 2019.