Antibiotic resistance is a significant emerging health threat. Exacerbating this problem is the overprescription of antibiotics as well as a lack of development of new antibacterial agents. A paradigm shift towards the development of non-antibiotic agents that target the virulence factors of bacterial pathogens is one way to begin to address the issue of resistance. Of particular interest are compounds targeting bacterial toxins that protect against toxin-induced pathology without harming healthy commensal microbial flora. Development of successful anti-toxin agents would likely decrease the use of antibiotics, thereby reducing selective pressure that leads to resistance mutations. In addition, anti-toxin agents are not only promising for therapeutic applications, but also can be used as tools to study the role of toxins in bacterial pathogenesis. This work highlights strategies to combat two pathogenic bacteria by specifically targeting and neutralizing virulence factors that cause human disease. Toxin B (or TcdB) is elaborated by the bacterium Clostridioides (formerly Clostridium) difficile, an opportunistic bacterial pathogen that is a prevalent cause of nosocomial infections. Botulinum neurotoxins (BoNTs) from Clostridial spp. are the causative agents of botulism, a life-threatening flaccid paralysis caused by toxin internalization with or without an accompanying bacterial infection. Both TcdB and BoNTs are multidomain proteins that contain a protease domain. TcdB contains a cysteine-protease domain important for autoprocessing and BoNT contains a zinc-dependent metalloprotease domain that cleaves host proteins important for the propagation of neuronal action potentials. We hypothesized that cell-permeant, small-molecule inhibitors of the protease domains of these toxins would mitigate bacterial pathology in the host. Using activity-based probes to screen for covalent modifiers of reactive active site and active- site adjacent cysteines of TcdB and BoNT, we identified a preference for selenide-based small-molecule inhibitors for both toxins. We show that the parent selenide, ebselen, inhibits TcdB and BoNT by forming an irreversible covalent selenium-cysteine bond. Biochemical, cell-based, and animal model studies revealed nanomolar protection by ebselen and its analogs against toxin-induced pathology for BoNT and TcdB. Together, these data identify a class of selenide small-molecules that are cell-permeant, non-toxic and active against multiple bacterial toxins that can also be used to study the roles of these toxins in bacterial pathogenesis. Further, these compounds are ideal candidates for potential development as broad-spectrum antivirulence agents.