Objective The objective of this study was to investigate whether histamine H4 receptor (H4R) antagonists could prevent experimental periodontitis (EP)‐induced histological, functional and inflammatory alterations in submandibular gland (SMG), periodontal bone and gingiva. Methods Bilateral EP was induced for 2 weeks in anaesthetized male rats. The effect of systemic and local administration of H4R antagonists (JNJ7777120, JNJ10191584) on histopathology and functionality of SMG, bone loss and gingival inflammation was evaluated. Results The subcutaneous administration of JNJ7777120 prevented periodontitis‐induced SMG histological injury, reducing vacuolization and apoptosis and additionally reversed the increased prostaglandin E2 (PGE2) levels in SMG while it partially reversed the methacholine‐induced salivation reduction produced by periodontitis. JNJ7777120 attenuated bone loss and the increased PGE2 levels and inflammatory infiltration in gingival tissue of rats with periodontitis. Finally, local administration of JNJ7777120 and JNJ10191584 was also beneficial for improving periodontal parameters. Conclusions H4 receptor antagonists are able to ameliorate periodontitis‐induced injury on SMG, gingival tissue and bone structure, suggesting that pharmacological targeting of H4R could be an attractive strategy to improve periodontal health.