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Systemic dissemination of inflammation-related proteins has been linked to unhealthy ageing and increased mortality. Yet, the systemic inflammatory profile of periodontitis, a common oral inflammatory disease, remains poorly characterised. The aim of this study was to evaluate the existing evidence linking alterations in serum levels of inflammation-related proteins to periodontitis. This study was registered in Prospero (CRD42024597308). The inclusion criteria were original, English language studies of human participants ≥16 years that assessed serum biomarkers in individuals with periodontitis and periodontally healthy controls. PubMed, Scopus, and Web of Science were searched on October 13, 2024, and complemented with a hand search. Two independent reviewers performed abstract screening, full-text assessment, risk-of-bias assessment (modified Newcastle-Ottawa Scale), and extraction of summary data. A random-effects meta-analysis was performed to estimate the ratio of mean protein (RoM) level between periodontitis cases and controls. From 9120 screened records, 206 studies were included in the qualitative data synthesis, yielding 17953 participants (157 unique proteins) in total. Data from 144 studies (39 proteins) were included in the meta-analysis. In individuals with periodontitis compared with controls, analyses showed significantly (P<0.05) higher levels of C-C motif chemokine ligand 2 (CCL2); interleukin (IL)-1β, IL-6, IL-17, IL-17A and IL-18; leptin; matrix metalloproteinase 8 (MMP-8), myeloperoxidase (MPO); receptor activator of nuclear factor kappa-Β ligand (RANKL); and tumour necrosis factor α (TNF-α). Notably, CCL2, IL-1β, IL-6, IL-17, IL-17A, MMP-8, RANKL and TNF-α remained significantly elevated even in analyses restricted to systemically healthy participants, with additional significant associations observed for IL-12 and IL-33. Periodontitis is, independently of comorbidities, associated with systemic inflammation and with specific cytokines involved in metabolic and immune dysregulation, including inflammaging. These findings highlight the systemic impact of periodontitis and the importance of reducing the inflammatory burden to promote healthy aging and longevity.