Matrix metalloproteinase (MMPs) are a family of zinc and calcium dependent endopeptidases. All MMPs have two molecular appearances, one is pre-peptide sequence that directs their secretion in the extracellular environment and another is pro-peptide domain that maintains them in their zymogenic form. MMPs play crucial roles in numerous pathophysiological conditions, including cancer, cardiovascular disease, autoimmune diseases, skin aging, inflammation, etc. Modulating MMP activities at transcription levels, proteolytic activation of the zymogen form, and inhibition of the active enzyme may however be useful therapeutic approaches. Although several synthetic MMP inhibitors have been identified as cytostatic, antiangiogenic, antiaging, and antiwrinkle agents and also subjected to preclinical trials, but there are consistent number of disappointments and adverse reactions. Currently, researchers are paying great deal of attention on identifying new molecular entities from nutraceuticals which includes genistein, myricetin, curcumin, xanthorhizzol, theaflavin, resveratrol, matlystatin B, nicotinamide, betulinic acid, oleanolic acid, glycyrrhetinic acid, catechin derivatives, etc. to target specific MMPs. Importance of these phytomolecules remains largely underexploited, despite increasing evidences showing their ability to act synergistically to control MMPs. This chapter highlights the recent information and investigations on natural MMP inhibitors as novel therapeutic intervention.