Background: Rapid maxillary expansion (RME) is a commonly used orthopedic method in orthodontics that may influence upper airway physiology. However, its effects on inflammation in sinusitis have not been clearly identified. This study aimed to evaluate the impact of RME on experimentally induced sinusitis in rats using biochemical and histopathological markers. Objectives: To investigate the effects of RME on inflammatory cytokine levels (neopterin, IFN-γ, IL-6, TNF-α) and histopathological changes in rats with sinusitis. The secondary objective was to analyze histological changes in the sinus epithelium. Methods: Thirty-two male rats were divided into four groups (Control, Sinusitis, RME, RME+Sinusitis). Sinusitis was induced using Staphylococcus aureus. RME was performed using a helical spring appliance applying 120 g force for 5 days, followed by a 10-day retention period. Serum cytokines were analyzed by ELISA. Histopathological evaluation was conducted on hematoxylin-eosin stained sections. One-way ANOVA and Tukey post hoc tests were used (P < 0.05). Results: RME significantly reduced neopterin, IL-6, and TNF-α levels in rats with sinusitis. Histopathological analysis showed decreased PMNL infiltration, fibroblast activity, and epithelial damage in the RME+Sinusitis group compared to the Sinusitis group. Conclusions: RME application reduced inflammation and tissue damage in rats with induced sinusitis, suggesting a potential therapeutic role in upper airway inflammatory conditions.