There are many treatment protocols for relieving pain and accelerating oral ulcer healing. The purpose was to evaluate the anti-inflammatory and antimicrobial effect of silver nanoparticle (AgNP) gel on oral ulcers compared with the traditional treatment in animal model. In this experimental study, 72 adult male rats were randomly allocated into four groups, after ulcer induction: control (receive no treatment), placebo (placebo gel was applied on ulcers once daily), triamcinolone (ulcers were treated with triamcinolone paste once daily), and AgNPs (ulcers were treated with AgNP gel once daily). The animals were sacrificed at three successive periods of 3, 7, and 14 days after ulcer induction. Histopathological scores of re-epithelialization and degree of inflammation were assessed. The wound size was measured clinically. For parametric data, the analysis of variance, and for ordinal histopathological data, the Kruskal-Wallis test using SPSS was done. A P < 0.05 was considered statically significant. Control and placebo groups had no case of complete healing. Improvement of wound size by triamcinolone paste was not significant in different days but showed significant differences in degree of inflammation (P < 0.001) and re-epithelialization (P = 0.012). Reduction of wound size by AgNPs gel had significant difference at 14th day (P < 0.001); further, by this gel, significant differences in degree of inflammation and re-epithelialization were seen in long-term medication. AgNP gel could be effective in oral ulcer healing clinically and histopathologically. Although this gel showed delayed effect, it had better healing effect according to the cases with complete healing. Hence, the application of AgNP oral gel can be considered as an alternative approach for oral ulcers.