Background: Periodontitis (PD) and rheumatoid arthritis (RA) are chronic inflammatory conditions, characterized by dysregulated immune response and excessive production of inflammatory mediators. The oral disease PD is triggered by periodontal pathogens, leading to the destruction of tissues surrounding the teeth, whereas RA is a systemic autoimmune disease primarily affecting the joints. The objective of this study was to investigate the prevalence of PD and map the profile of salivary and serum inflammatory mediators of patients with RA, with respect to periodontal severity (PD stage II and PD stage III/IV). Methods: For this cross-sectional cohort study, 62 patients diagnosed with RA were recruited. All participants underwent a full-mouth dental examination. Levels of various inflammatory mediators, including tumor necrosis factor (TNF) superfamily proteins, interferon (IFN) family proteins, regulatory T cell (Treg) cytokines, and matrix metalloproteinases were determined in saliva and serum samples from each participant using a human inflammation multiplex immunoassay panel. Results: In the current RA cohort, all participants were diagnosed with PD, of which 35.5% were classified as PD stage II and 64.5% as PD stages III/IV. Inflammatory mediator levels were significantly higher in both saliva and serum samples from patients with RA and PD stages III/IV, compared to those with RA and stage II within the same cohort. These included higher serum levels of sCD30, IL-10, IL-19, osteopontin and elevated salivary levels of BAFF/TNFSF13B and IFN-α2. Additionally, APRIL/TNFSF13 levels were increased in both saliva and serum. Conclusions: Among the studied patients with RA, the majority exhibited severe PD (stage III/IV), underscoring the importance of periodontal prophylaxis and treatment for this group of patients. Higher levels of inflammatory mediators were observed in both saliva and serum in those with PD stages III/IV, suggesting a potential link between the severity of PD and systemic inflammation in RA. Further research is needed to explore the clinical implications of these findings.