Matrix metalloproteinases (MMPs) are proteolytic enzymes involved in extracellular matrix (ECM) degradation, contributing to various pathological conditions, including periapical lesions and periodontal diseases. This systematic review evaluates the inhibitory effects of different natural and synthetic MMP inhibitors on MMP-2 and MMP-9 activities in mammalian cells, which are critical enzymes implicated in ECM breakdown. A comprehensive literature search was performed across databases, including PubMed, Scopus, and Cochrane until June 2023, following PRISMA guidelines. The Office of Health Assessment and Translation (OHAT) risk of bias tool was used for quality assessment, revealing a low risk of bias across all studies. Our findings demonstrate that both natural and synthetic MMP inhibitors significantly reduce MMP-2 and MMP-9 activities in mammalian cells. These compounds offer potential therapeutic benefits in managing diseases characterized by excessive MMP activity, such as periapical lesions and periodontal disease. This review highlights the therapeutic potential of MMP inhibitors in dentistry, specifically focusing on the promising roles of natural and synthetic MMP inhibitors in protecting ECM integrity.