Background Hypotension and bradycardia are the most common complications after spinal anesthesia. The aim of this study is to compare the effects of prophylactic ephedrine versus prophylactic ondansetron on postspinal hemodynamic changes in percutaneous nephrolithotomy operation. Patients and methods A total of 100 patients were included in this randomized study. Patients were selected to receive either prophylactic intravenous ephedrine 15mg immediately after spinal anesthesia (group E) or intravenous ondansetron 6mg (group O) 5 min before spinal block. Demographic data, American Society of Anesthesiologists physical status, duration of surgery, mean arterial pressure, heart rate measurements (basal, immediately after block, and then every 5 min till the end of operation), incidence of nausea and vomiting, incidence of shivering, and other complications were recorded. Moreover, intraoperative extraephedrine doses and atropine administration were recorded. Results There were no significant differences between the groups regarding demographic data, American Society of Anesthesiologists physical status, and duration of surgery. Although mean arterial pressures and heart rate were lower in groupO, there was no significant difference between both the groups in most measurements or in the proportion of patients experiencing hypotension and ephedrine requirements. There was a significant difference between both groups regarding incidence of nausea and vomiting (P=0.019) and in the incidence of shivering (P=0.002). Conclusion Prophylactic ondansetron 6mg 5 min before spinal anesthesia for percutaneous nephrolithotomy operation is comparable to prophylactic 15mg ephedrine immediately after block in attenuating the incidence of hypotension and bradycardia and in the division of patients in need of a rescue vasoconstrictor during surgery.