Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that play a major role in extracellular matrix (ECM) components degradation, enabling tissue remodeling and cellular migration. In cancer, overexpression and activation of MMPs, leadingly MMP-2 and MMP-9, contribute to tumor progression, invasion, metastasis, angiogenesis, and modulation of the tumor microenvironment. This article provides insights into the mechanisms of MMP regulation, including the influence of oncogenic signaling pathways, cytokines, growth factors, and hypoxic conditions within the tumor niche. The complex interplay between MMPs and their inhibitors is discussed. Furthermore, we explore a broad spectrum of MMP inhibition strategies, ranging from synthetic inhibitors and monoclonal antibodies to emerging natural compounds, such as flavonoids and nonsteroidal anti-inflammatory drugs (NSAIDs), highlighting their potential to modulate MMP activity with reduced toxicity. Although several synthetic MMP inhibitors have failed in clinical trials due to off-target effects and poor efficacy, recent advances in in-silico screening, drug repurposing, and combination therapies offer renewed promise. In conclusion, targeting MMPs through a multifaceted and personalized approach could significantly enhance the efficacy of current cancer therapies, reduce metastasis, and improve patient outcomes. Future research should focus on refining inhibitor specificity and validating combinatorial treatments in preclinical and clinical settings.