Matrix metalloproteinases (MMPs) cleave extracellular matrix proteins, growth factors, cytokines, and receptors to influence organ development, architecture, function, and the systemic and cell-specific responses to diseases and pharmacological drugs. Conversely, many diseases (such as atherosclerosis, arthritis, bacterial infections (tuberculosis), viral infections (COVID-19), and cancer), cholesterol-lowering drugs (such as statins), and tetracycline-class antibiotics (such as doxycycline) alter MMP activity through transcriptional, translational, and post-translational mechanisms. In this review, we summarize evidence that the aforementioned diseases and drugs exert significant epigenetic pressure on genes encoding MMPs, tissue inhibitors of MMPs, and factors that transcriptionally regulate the expression of MMPs. Our understanding of human pathologies associated with alterations in the proteolytic activity of MMPs must consider that these pathologies and their medicinal treatments may impose epigenetic pressure on the expression of MMP genes. Whether the epigenetic mechanisms affecting the activity of MMPs can be therapeutically targeted warrants further research.