Objective Perioperative shivering is a very common complication. Despite the vast array of knowledge regarding perioperative shivering and its after-effects, its prophylaxis is often overlooked. The study aims to compare the efficacy and safety of low-dose ketamine, ondansetron, and pethidine in the prevention of perioperative shivering in patients undergoing total knee replacement surgery under the subarachnoid block. Methods In this randomized controlled study, 203 patients aged 18-75 were included and allocated to one of the 4 groups; normal saline (group S), ondansetron 4 mg (group O), ketamine 0.25 mg kg −1 (group K), and pethidine 0.25 mg kg −1 (group P). Side effects, namely hypotension, nausea and vomiting, sedation, hallucinations, and respiratory depression were recorded. Results Perioperative shivering was present in 22 (44%), 8 (16%), 4 (7.84%), and 4 (7.69%) patients respectively in group S, O, K, and P, which was statistically significant when compared to group S with group K and P ( P < .01). No difference in the incidence of hypothermia was observed across the groups ( P < .17). A significantly lower incidence of hypotension was observed in group K. In group K, 5.9% of the patients were scored as being under severe sedation, according to the modified Wilson sedation scale. There was no incidence of hallucination or respiratory depression observed in any of the groups. Conclusions Patients undergoing total knee replacement surgeries are highly predisposed to the development of hypothermia. Temperature monitoring is thus imperative for all patients. Prophylactic administration of low-dose ketamine or ondansetron or low-dose pethidine produces a significant anti-shivering effect without any significant side effects. However, low-dose ketamine has the advantages of a lower incidence of hypotension, nausea, and vomiting than pethidine.