Background. Performing spinal anesthesia with at least hemodynamic variation and complications is always challenging for anesthesiologists. In this study, we investigated the effect of ephedrine and placebo on hemodynamic changes in patients undergoing percutaneous nephrolithotomy with spinal anesthesia. Methods. This randomized, double-blind prospective clinical trial was conducted on 120 patients aged 20‒60 years with ASA (American Society of Anesthesiologists) classes I and II. Patients who were candidates for percutaneous nephrolithotomy with spinal anesthesia were divided into intervention (received 1 cc = 5 mg ephedrine) and control groups (received 1 cc normal saline). All vital parameters, including HR (heart rate) and NIBP (noninvasive blood pressure), were recorded perioperatively T0–T25) and finally at the end of surgery time (Tf). The results were analyzed by SPSS software version 23, and a P value ≤0.05 was considered significant. Results. The mean arterial pressure during surgery between T3 and T9 and the mean heart rate in times of T3–T8 in the intervention group were higher than in the control group, and this difference was statistically significant ( P < 0.05 ). The incidence of hypotension, bradycardia, nausea, and vomiting and the amount of prescribed ephedrine, atropine, and ondansetron in the control group were higher than in the intervention group ( P = 0.001 ). Seven patients in the control group and four in the intervention group had shivering, but this difference was not statistically significant ( P = 0.43 ). Conclusion. This study showed the effectiveness of the prescription of 5 mg ephedrine two minutes before changing from the lithotomy position to the supine in maintaining hemodynamic stability, reducing hypotension, bradycardia, nausea, and vomiting, and the amount of prescribed ephedrine, atropine, and ondansetron. Trial Registrations. This trial is registered with IRCT20160430027677N22.