Cancer　is　characterized　by　the　uncontrolled　proliferation　of　cells　that　can　invade　and　metastasize　to　distant　organs,　with　metastasis　accounting　for　over　90　%　of　cancer-related　mortalities.　The　urokinase-type　plasminogen　activator　receptor　(uPAR),　a　critical　hub　for　cancer　proliferation　and　metastasis,　angiogenesis,　and　inflammation,　emerges　as　a　promising　anti-cancer　and　anti-metastasis　target.　Developing　small-molecule　inhibitors　that　disrupt　the　interaction　between　uPAR　and　its　ligand,　urokinase-type　plasminogen　activator　(uPA),　constitutes　a　major　focus　in　anticancer　drug　discovery.　This　review　collates　studies　on　uPAR-targeted　small-molecule　inhibitors　published　over　the　past　three　decades　in　a　comprehensive　manner.　We　categorize　the　reported　inhibitors　by　core　chemical　scaffolds　and　analyze　their　roles　in　disrupting　tumor-associated　angiogenesis　and　inflammatory　signaling,　to　elucidate　the　structure-activity　relationships　(SAR)　of　these　compounds　against　uPAR.　Furthermore,　we　discuss　current　research　progress,　address　challenges,　and　evaluate　the　potential　of　computer-aided　drug　design　to　accelerate　uPAR　inhibitor　development.　This　review　may　not　only　pave　the　way　for　novel　uPAR　inhibitors　but　also　highlights　their　broader　therapeutic　implications　in　modulating　the　tumor　microenvironment.　©　2024