S-nitrosoglutathione (GSNO) is a nitric oxide (NO) donor, which exerts antioxidant, anti-inflammatory, and microbicidal actions. Intragingival application of GSNO was already shown to decrease alveolar bone loss, inflammation and oxidative stress in an experimental periodontal disease (EPD) model. In the present study, we evaluated the potential therapeutic effect of topical applications of hydroxypropylmethylcellulose (HPMC)/GSNO solutions on EPD in Wistar rats. EPD was induced by placing a sterilized nylon (3.0) thread ligature around the cervix of the second left upper molar of the animals, which received topical applications of a HPMC solutions containing GSNO 2 or 10 mM or vehicle (HPMC solution), 1 h prior to the placement of the ligature and then twice daily until sacrifice on day 11. Treatment with HPMC/GSNO 10 mM solution significantly reduced alveolar bone loss, oxidative stress and TNF-α e IL-1β levels in the surrounding gingival tissue, and led to a decreased transcription of RANK and TNF-α genes and elevated bone alkaline phosphatase, compared to the HPMC group. In conclusion, topical application of HPMC/GSNO solution is a potential treatment to reduce inflammation and bone loss in periodontal disease.