Background: Postoperative sore throat (POST) is a common occurrence following general anesthesia with endotracheal intubation although clinicians often regard it as a minor complication. The incidence of POST is estimated to be 21%–65% in different studies. The administration of the drug through aerosol route gained popularity among anesthesiologists with good acceptance from the patients. Hence, we conducted the study with the aim to compare the efficacy of preoperative nebulization with 4% lignocaine and ketamine, in the prevention of POST. Materials and Methods: The study is a prospective, randomized double-blinded study comparing the effects of comparison between preoperative nebulization with ketamine and 4% lignocaine in preventing POST. Hemodynamic parameters, Ramsay sedation score, and visual analog scale (VAS) at 0, 6, and 24 h were observed in both groups. Results: Ketamine nebulization provides better prophylaxis against the occurrence of moderate-to-severe POST as compared to lignocaine. At 0 h, none of the patients had ST in both the groups; at 6 and 24 h, the ST was significantly higher in lignocaine group (28.9% and 8.9%) as compared to ketamine group (8.9% and 0%), with P = 0.04. Mild, moderate, and severe VAS was observed in 51%, 33%, and 16% of Group 1, respectively, while in Group 2, it was observed in 16%, 36%, and 49% of study population, respectively, and this difference was statistically significant. Conclusion: Patients undergoing surgery under general anesthesia with endotracheal intubation were benefitted from ketamine nebulization as prophylaxis against moderate-to-severe POST.