Introduction Postanesthesia shivering (PAS) is one of the most common complications after surgeries. There are two methods to reduce the shivering, including pharmacological and nonpharmacological methods. Aim This study compared the efficacy and safety of 4-mg oral ondansetron premedication on preventing PAS, perioperative core body temperature changes, and hemodynamic stability. Patients and methods This prospective, observational study consisted of 100 adult patients scheduled for general surgery or interventional structural heart disease. The patients were randomized into two groups of 50 patients each. Group I received 4 mg of oral ondansetron, and group II received an oral placebo 60–90 min before the operation. All patients were assessed for perioperative hemodynamic changes, core body temperature changes, and PAS. Results Regarding the efficacy of the preoperative administration of oral ondansetron, this study reports the valuable preventive effect on shivering for ondansetron group (8.1%) compared with control group (44.3%), and there was a highly significant difference between both groups according to the incidence and scoring of shivering. On the contrary, we found no significant difference between groups according to heart rate, systolic blood pressure, and diastolic blood pressure. However, reduction in systolic blood pressure and diastolic blood pressure was recorded in both groups after induction, which came back up at the end of surgery. In addition, tympanic temperature reduction was recorded intraoperatively and came back up during the recovery period, with no statistically significant differences between groups. Conclusion Oral ondansetron premedication adequately decreases PAS compare with placebo. Ondansetron does not have any significant effect on the core or peripheral temperature.