Background: Premedication with oral melatonin and clonidine reduces anxiety and prolongs the postoperative analgesia. But there are few studies that have observed the isoflurane consumption when they are given as premedication, hence this study was conducted to compare the isoflurane consumption and duration of analgesia when oral melatonin and clonidine is given as premedication. Methods: Eighty-four patients whose aged between 18 and 60 years of American Society of Anesthesiologists one and two, undergoing surgery under general anesthesia were randomly allocated into three groups of 28 each. Group C received placebo (sugar pellet), Group M melatonin 3 mg orally and Group Cl clonidine 100 μg orally 60 min before surgery. Results: The end tidal isoflurane concentration at 30 min [Group C 0.78 (0.21), Group M 0.48 (0.15), Group Cl 0.64 (0.16) (p < 0.001)], at 60 min [Group C 0.75 (0.16), Group M 0.53 (0.2), Group Cl 0.64 (0.12) (p < 0.001 )] was lower in Group M compared to Group Cl and C. Isoflurane consumption at 30 min [Group C 6.24 (1.3), Group M 3.84 (0.75), Group Cl 4.96 (0.98) (p < 0.001)] and at 60 min [Group C 10.8 (2.18), Group M 7.65 (1.11), Group Cl 9 (2.45) (p < 0.001)] was lower in Group M compared to Group Cl and C. Duration of analgesia was 267.60 ± 81.66 min in Group C, 507.00 ± 136.11 min in group M and 438.60 ± 111.01 min in Group Cl (p < 0.001). Conclusion: Premedication with oral melatonin resulted in lower end tidal isoflurane concentration and isoflurane consumption, however it did not prolong the duration of analgesia when compared with oral clonidine.