Purpose: The purpose of the present study was to compare the effect of intramuscular masseter administration of methylprednisolone using a split-mouth design, as a single 20-mg dose, after removal of impacted lower third molars. Patients and Methods: A non-blind, cross-over, comparative, non-randomized, clinical trial was planned. The sample was composed of 32 patients requiring extraction under local anesthesia of two lower bony impacted mandibular third molars. The difficulty of extraction was similar in all cases. The patients received 20 mg of methylprednisolone injected into the masseter muscle via the intrabuccal approach, immediately after suturing of the surgical wound on the right side. The left side received no intramuscular corticoid. Evaluations were made of postoperative pain and swelling. Results: A total of 32 subjects requiring surgical removal of two impacted mandibular third molars under local anesthesia were included in the present study. The patients administered methylprednisolone showed superior results after surgery in terms of pain and facial swelling parameters using self-evaluation, with statistically significant differences versus the control-side (p < 0.05). The results obtained show that 20 mg of methylprednisolone injected into the masseter muscle in the immediate postoperative period reduces swelling and pain. Conclusions: Injection of methylprednisolone is an effective therapeutic strategy to reduce swelling and pain after surgical removal of impacted lower third molars. It offers a simple, safe, painless, noninvasive, and cost effective therapeutic option for moderate and severe cases.