MMPs can be activated by cleavage of the propeptide by already activated members of the MMP family or through other serine proteases that cleave peptide bonds within MMP prodmains. More than one-third of human MMPs are capable of being activated by proprotein convertases or furins; this process is the conversion of the zymogen into an active proteinase. These MMPs consist of a furin sequence between their catalytic and pro domains. Several proMMPs are activated in the secretion pathway by furin proprotein convertases.

MMPs can also be activated by chaotropic agents, heat, low pH, and thiol-modifying agents (4-aminophenylmerurcin acetate, N-ethylmaleimide and mercury chloride, which causes disruption of the cysteine-Zn2+ complex.