In this paper, three key findings emerge from our study: First, 19 natural compounds are discovered against MMPs by using structure-based screening and in vitro biologically assay. These compounds have diverse structures and differ from well-known general peptidomimetic and non-peptide hydroxamate inhibitors. Second, the qualitative analyses of SAR and selectivity trends among six different MMPs are also taken to compare the protein sequences and crystal structures. We find that the hydroxycinnamic acid moiety, the common structure in our natural compounds, can generate many key interactions which make the compounds specifically bind with MMPs enzymes. In addition, through the analysis of the overlaid MMP structures, we do see that the shape and size of the S1’ pocket may be the crucial factor for determining the selectivity of MMP inhibitors. Third, Compound 5, the most potent inhibitor in MMPs enzymic assay, also represses the MMP-2 and active-MMP-9 expression in MDA-MB-231 cancer cell and suppresses the migration of MDA-MB-231 in a wound healing assay. A hit-to-lead compounds structure optimization based on the compound 5 is undertaken. We believe that the active natural compounds discovered in this study can provide novel scaffolds for more potent and highly selectivity compounds against MMPs