Matrix metalloproteinases (MMPs) are a family of endopeptidases recognized for their involvement in the degradation of the extracellular matrix and their important role in the pathogenesis of periodontitis. This chronic inflammatory condition causes the degradation of dental supporting tissues, resulting in bone loss. In patients with periodontitis, the expression and activation of MMPs, especially MMP-8 and MMP-9, significantly influence tissue degradation. In periodontitis treatment, various natural or synthetic metalloproteinase inhibitors (MMPIs) and antibiotics are used in sub-antimicrobial doses. However, while the evidence supports a role for MMPIs in reducing inflammation, preserving connective tissue, and improving the results of conventional periodontitis treatment, their clinical application is limited. In this review, we summarize MMPIs, their characteristics, and the mechanisms of action that may support their use in the treatment of periodontitis. In conclusion, MMPIs are a therapeutic alternative with great potential in the management of periodontitis, especially when combined with mechanical treatments, although further research is needed to optimize their clinical use.