Introduction Pain, swelling, trismus, and dry socket are common postoperative complications of mandibular third molar surgery (MTMS), which is a routine minor oral surgical procedure. The purpose of this study was to compare the efficacy of the combination of bromelain, rutocide, and trypsin versus serratiopeptidase in reducing postoperative sequelae after MTMS. Materials and methods It was a pilot study conducted from October 2022 to May 2023 in the outpatient department of a private dental institution. Patients with horizontal position C mandibular third molar impaction were enrolled, and a surgical procedure was performed. Patients were divided into two groups. Group A received tab Rutocide D (trypsin 48mg, bromelain 90mg, rutoside 100mg, and diclofenac 50mg) twice daily, and Group B received tab Zerodol SP (aceclofenac 100mg, paracetamol 325mg, and serratiopeptidase 15mg) twice daily in the postoperative period of five days. Outcome parameters like pain, using the visual analog scale (VAS), and mouth opening, were measured on postoperative days one and seven. An Excel spreadsheet (Microsoft, Redmond, WA, USA) was used for data entry and statistical analysis was performed using SPSS (version 23.0; IBM Corp., Armonk, NY, USA). The patients included in the study were analyzed postoperatively. The statistical significance was set at p < 0.05. An independent sample t-test was used to assess the variables between groups. Results The data analyzed showed that the pain perception in Group A was less when compared to Group B. On postoperative day one, the mean VAS score in Group A was 4.0 ± 0.3 and in Group B was 5.2 ± 0.4. On postoperative day seven the mean VAS score in Group A was 1.4 ± 0.43 and in Group B was 3.0 ± 0.4. The results were statistically significant with less pain experienced by participants in Group A compared to participants in Group B on both postoperative day one and postoperative day seven. On the first postoperative day, patients in Group A had a mean mouth opening of 33.68 ± 1.42, whereas patients in Group B had a mean mouth opening of 29.41 ± 1.86, which was statistically significant. Similarly, on postoperative day seven, patients in Group B had a mean mouth opening of 31.73 ± 3.27, whereas patients in Group A had a mean mouth opening of 36.32 ± 0.24, which was statistically significant. Conclusion It is concluded that the proteolytic enzyme combination of trypsin, bromelain, and rutocide is more efficacious than serratiopeptidase in reducing postoperative sequelae after MTMS.