<p>SARS-CoV-2 vaccination or infection may not protect from future novel coronavirus outbreaks. Although several drugs targeting essential coronavirus proteins are broadly effective, the error-prone coronavirus RNA-dependent RNA polymerase and a rapid viral replication cycle mean that drug resistance will likely emerge. Small molecules that target sequence-stable host proteins could offer more durable pan-coronavirus activity. Here, we show that the well-tolerated and orally bioavailable small molecule SH-BC-893 protects from endosomal, but not plasma membrane, entry by diverse coronavirus strains. SH-BC-893 alters endolysosomal trafficking similar to PIKfyve inhibitors and, like hydroxychloroquine, reduces cathepsin L activity. While all three compounds block endosomal entry mediated by coronavirus spike proteins in vitro, PIKfyve inhibitors and chloroquine derivatives are ineffective or even increase viral titer in vivo. In contrast, SH-BC-893 reduced viral titer in the lungs of mice infected intranasally with the LD50 of the MHV-1 coronavirus by 3 logs. Thus, poor in vivo outcomes when using apilimod or chloroquine as anti-virals likely reflect pharmacologic limitations of these compounds rather than a flawed therapeutic strategy. We anticipate that SH-BC-893 or optimized analogs with similar tissue pharmacology could control infections by novel coronaviruses, particularly if given in combination with TMPRSS2 inhibitors to block entry at the plasma membrane, an obvious escape pathway. Because it targets host rather than viral proteins, SH-BC-893 might also block infection by many other viruses that enter via endosomal pathways: orthomyxoviruses (influenza), filoviruses (Ebola, Marburg), flaviviruses (Dengue, Zika, and West Nile), alphaviruses (Chikungunya) rhabdoviruses (rabies), and bunyaviruses (Hantaan or Sin Nombre). In sum, further evaluation of SH-BC-893 and/or optimized analogs as potential pan-antiviral agents is merited.</p>