Background: Ondansetron and Dexmedetomidine are recently used effectively to prevent shivering following spinal anesthesia. Objectives: This study compares the effects of weight-adjusted doses of Ondansetron and Dexmedetomidine in preventing post-spinal shivering and its subsequent hazards in cases who underwent elective transurethral resection of the prostate (TURP). Methods: In this prospective randomized double-blind controlled trial, 132 ASA (I, II) patients who were scheduled to undergo TURP were divided into 3 equal groups (44 each): Control group: received 5 ml of normal saline (0.9%) intravenously after SA; Group D: received 1 ug/kg. Dexmedetomidine was intravenously diluted in 5 mL of normal saline after SA. Group O received (0.1 mg/kg) Ondansetron intravenously diluted in 5 mL of normal saline after SA. Shivering occurrences, intensity, and duration (primary outcome), hemodynamics and core temperature changes, sedation level, total consumed rescue pethidine, and intraoperative complications were evaluated. Results: There was a statistically non-significant difference between Ondansetron and Dexmedetomidine as regard to shivering occurrences, intensity, and duration, while it was significant when compared to the control group. Hemodynamics showed a significant decrease in heart rate in Dexmedetomidine while compared to the Ondansetron and Control groups. Additionally, sedation levels were significantly higher in the dexmedetomidine group compared to other groups. However, there was a significant increase in total consumed rescue pethidine in the control group when compared to other groups. When compared to both the Dexmedetomidine and control groups, the Ondansetron group had a significantly lower risk of hypotension. Conclusions: The prophylactic IV weight-adjusted dose of Ondansetron is as effective as IV Dexmedetomidine in reducing the shivering occurrences, intensity, duration, and total of rescue pethidine doses in patients undergoing TURP. The IV weight-adjusted dose of Ondansetron is associated with more hemodynamic stability compared to IV Dexmedetomidine, with fewer incidences of bradycardia and hypotension.