In spite of advances in root canal therapy and better knowledge of pulpal and periapical inflammation, up 40% of endodontic patients report varying degrees of pain. The aim of this present study was to compare the effect of single preoperative dose of ibuprofen or dexamethasone on post-endodontic pain. Sixty volunteers were divided into three groups (n=20 per group): PL, placebo; IB, 400 mg of ibuprofen; and DE, 8 mg of dexamethasone. The primary outcome was the post-endodontic pain intensity measured with a numerical rating scale (4, 8, 12, 24, and 48 h). Secondary outcomes included number of anesthetic cartridges used and consumption of rescue medication. Data were analyzed by one-way ANOVA, chi-square and Kruskal-Wallis tests. There was no significant difference among groups (p>0.05) considering the pain intensity. Only 37% of IB group patients and 28% of DE group patients used some rescue medication. On the other hand, 74% of PL group patients mentioned the consumption of rescue medication; PL group had a statistically significant difference (p<0.05) in comparison with IB and DE groups. The number of anesthetic cartridges used had no statistically significant difference among the groups (p>0.05). Significant differences were not found in the reduction of pain intensity and the number of anesthetic cartridges used. Considering the consumption of rescue medication (secondary outcome), preoperative administration of Ibuprofen or dexamethasone reduces post-endodontic pain and discomfort in comparison with a placebo. Premedication with anti-inflammatory drugs drugs could be contributed to control of the post-endodontic pain, mainly in patients more sensible for pain.