Background: Arthroscopic knee surgeries are very common procedures as ambulatory day case surgeries and are preferred by most patients. Many patients complain of moderate to severe pain 24 h after surgery and pain affects the patient’s activity level and satisfaction. Post-operative pain is a frequent observation in patients undergoing knee arthroscopic surgeries and remains a challenge to anaesthesiologist. Objective: To assess the efficacy of preoperative duloxetine, melatonin and tapentadol for post spinal analgesia and sedation in knee arthroscopic surgeries. Methods: This prospective, randomized study was conducted at Anesthesia Department, Rahat Anwar Hospital, Band Road, Chandmari, Barishal, Bangladesh from June-2021 to December 2022. After Institutional Ethical Committee clearance and written informed consent in 106 American Society of Anesthesiologists (ASA) I and II patients of either sex between 18-60 years of age, posted for knee arthroscopic surgery under spinal anesthesia. Patients undergoing knee arthroscopic surgery requiring spinal anaesthesia were allocated randomly to four groups of oral Placebo Group A, 20 mg Duloxetine Group B, 3 mg Melatonin Group C, 100 mg Tapentadol Group D, 90 minutes before surgery. We assessed block characteristics, intraoperative sedation using Ramsay sedation scores, postoperative pain scores using Numeric Rating Score, time to use of first analgesic, 24-hours analgesic consumption, additional analgesic consumption and any adverse effects. Results: Total 106 patients Spinal anaesthesia was successfully performed. No significant difference in age, sex, weight and duration of surgery were found among the groups. Time to first post-operative analgesic request (477.96±97.85 min) and total diclofenac consumption (111.25±50.78mg) was significantly longer in Group D compared to Group A. Although post-operative pain assessed by NRS (numerical rating scale) was significantly lower in Group D as compared to Group A, B and C at 2 hours after surgery, no significant difference was observed at any time point among groups. Mean duration of post-operative analgesia was 477.96±97.85 minutes in Tapentodol Group (p value<0.001). Total 24 hours diclofenac consumption is minimum in Tapentodol Group (p 0.04). No statistical significant differences were present in the onset of the spinal block and Ramsay Sedation Score among the Groups. Conclusion: Preoperative administration of oral tapentadol provides prolonged analgesia with reduced 24-hours analgesic consumption.