Cancer　remains　one　of　the　most　pressing　challenges　to　global　healthcare,　exerting　a　significant　impact　on　patient　life　expectancy.　Cancer　metastasis　is　a　critical　determinant　of　the　lethality　and　treatment　resistance　of　cancer.　The　urokinase-type　plasminogen　activator　receptor　(uPAR)　shows　great　potential　as　a　target　for　anticancer　and　antimetastatic　therapies.　In　this　work,　we　aimed　to　identify　potential　uPAR　inhibitors　by　structural　dynamics-based　virtual　screenings　against　a　natural　product　library　on　four　representative　apo-uPAR　structural　models　recently　derived　from　long-timescale　molecular　dynamics　(MD)　simulations.　Fifteen　potential　inhibitors　(NP1-NP15)　were　initially　identified　through　molecular　docking,　consensus　scoring,　and　visual　inspection.　Subsequently,　we　employed　MD-based　molecular　mechanics-generalized　Born　surface　area　(MM-GBSA)　calculations　to　evaluate　their　binding　affinities　to　uPAR.　Structural　dynamics　analyses　further　indicated　that　all　of　the　top　6　compounds　exhibited　stable　binding　to　uPAR　and　interacted　with　the　critical　residues　in　the　binding　interface　between　uPAR　and　its　endogenous　ligand　uPA,　suggesting　their　potential　as　uPAR　inhibitors　by　interrupting　the　uPAR-uPA　interaction.　We　finally　predicted　the　ADMET　properties　of　these　compounds.　The　natural　products　NP5,　NP12,　and　NP14　with　better　binding　affinities　to　uPAR　than　the　uPAR　inhibitors　previously　discovered　by　us　were　proven　to　be　potentially　orally　active　in　humans.　This　work　offers　potential　uPAR　inhibitors　that　may　contribute　to　the　development　of　novel　effective　anticancer　and　antimetastatic　therapeutics.Communicated　by　Ramaswamy　H.　Sarma{GRAPHIACAL　ABSTRACT}