Introduction: Corticosteroids are considered anti-inflammatory which considered the essential roles, as well as it reduces edema. (1) Aim: To compare the efficacy of dexamethasone injection submucosally, intra-masseteric and intra-muscular on post-operative swelling, mouth opening and pain following removal of mandibular impacted third molars. Type of Study: prospective randomized comparative clinical study. Methods: The current study included forty-five patients with impacted mandibular third molars were selected to underwent surgical removal of mandibular third molars. Group I, comprised of fifteen patients who received pre-operative sub-mucosal 8 mg dexamethasone injection, Group II, comprised of fifteen patients who received pre-operative Intra-masseteric 8 mg dexamethasone injection and Group III, taking intramuscular dexamethasone injection, Postoperative assessment included: mouth opening, swelling as well as pain at the following intervals; 1st, 3rd and 7th day post-operative. Results: our study showed no statistically significant difference between mean MMO as well as VAS in Group I and II; both showed statistically significant higher mean MMO and VAS than Group III. Significant reduction in pain and swelling in both sub-mucosal, intra-masseteric and intra-muscular but a greater immediate effect on trismus was seen in sub-mucosal and intramasseteric routes Discussion: preoperative administration of dexamethasone has greater post-operative effects. Dexamethasone injected preoperatively was safe and simple effective method to reduce postoperative complications such pain, swelling and trismus.