Background <p>This systematic review aimed to synthesize findings from existing studies to explore the role of matrix metalloproteinases (MMPs), particularly MMP-9 and MMP-8, in the pathophysiology of cardiovascular disease (CVD) and periodontitis.</p> Methods <p>A comprehensive literature search was conducted across multiple electronic databases, including Medline, Scopus, Embase, Epistemonikos, and grey literature sources. Cross-sectional, cohort, and case-control studies that evaluated salivary MMP levels in patients with periodontitis and CVD were included. The Newcastle-Ottawa Scale was used to assess the quality and risk of bias of the included studies. Confounding factors were evaluated using a causal diagram and a confounder matrix.</p> Results <p>Eight studies with a total of 2,636 participants were included in the review. Elevated levels of salivary MMP-9 and MMP-8 were consistently observed in patients with both periodontitis and CVD, compared to healthy controls or patients with periodontitis alone. The imbalance between MMPs and their inhibitors, such as TIMP-1, was also evident in these patients, indicating dysregulated extracellular matrix remodeling. Salivary MMP levels were correlated with other inflammatory markers, including myeloperoxidase (MPO) and interleukin-1 beta (IL-1β), further supporting the interconnected nature of oral and systemic inflammation.</p> Conclusion <p>This review highlights the potential of salivary MMPs, particularly MMP-9 and MMP-8, as biomarkers for the early diagnosis, risk stratification, and monitoring of the interrelated conditions of periodontitis and cardiovascular disease. Further, longitudinal studies are warranted to elucidate the causal relationships between these biomarkers and disease progression.</p>