Objective <p>The aim of this review was to evaluate the influence of antidepressant use on inflammatory and clinical data related to periodontal status in animal and human studies.</p> Materials and methods <p>A systematic review was conducted according to the PRISMA guidelines. The potential risk of bias was assessed using the SYRCLE RoB or the Joanna Briggs Institute tools. For human studies, a meta-analysis was performed to compare periodontal parameters between users and non-users of antidepressants, and to estimate the mean difference using random effects models.</p> Results <p>Twelve studies met the inclusion criteria: eight were conducted on animal models, and four were human studies. Tianeptine, desipramine, imipramine, and fluoxetine effectively reduced alveolar bone loss in experimental periodontitis. Furthermore, desipramine, imipramine, and fluoxetine were observed to reduce the expressions of inflammatory markers in gingival tissue. The meta-analysis found no differences in the influence of antidepressant use on periodontal pocket depth, clinical attachment level, and gingival index between users and non-users. There was no standardization of the duration of use, type, and dosage of medication between studies.</p> Conclusions <p>Animal studies suggest antidepressants modulate the immunoinflammatory response and prevent alveolar bone loss in experimental periodontitis, but their impact on human periodontal status remains controversial. Standardized methods are needed to clarify antidepressant effects on the periodontium.</p> Clinical Relevance <p>This study informs health professionals that certain antidepressants may positively impact the periodontium, while also highlighting the need for further research evaluating their possible influence on the human periodontal condition and their potentially associated local/systemic adverse effects.</p>