There is an unmet need for effective respiratory virus antivirals and prophylactics to mitigate viral spread in the absence of available vaccines as well as reduce disease severity for at-risk patient groups. TMPRSS2 is an important human protease that recognizes viral particles and enables coronavirus and influenza virus infection, motivating multiple TMPRSS2 medicinal chemistry campaigns . However, selective TMPRSS2 inhibitors that completely avoid off-target effects on trypsin-like serine proteases, such as the coagulation pathway, have yet to be identified. In this study, we identified covalent small molecule inhibitors and noncovalent compounds with a novel amine scaffold as potential TMPRSS2 inhibitors. This collection of reagents and assays enabled us to rapidly screen for TMPRSS2 inhibition, kinetically characterize inhibitors, and determine high resolution cocrystal structures using a TMPRSS2 protein lacking its LDLR domain.