Invasive fungal infections due to Candida albicans, Aspergillus fumigatus and Cryptococcus neoformans, constitute a substantial threat to hospitalized, immunocompromised patients. Further, the presence of drug-recalcitrant biofilms on medical devices, and emergence of drug-resistant fungi such as Candida auris, introduce treatment challenges with current antifungal drugs. Worse, currently there is no approved drug capable of obviating preformed biofilms which increases the chance of infection relapses. Here, we screened a small molecule Prestwick Chemical Library, consisting of 1200 FDA approved off-patent drugs, against C. albicans, C. auris and A. fumigatus, to identify those that inhibit growth of all three pathogens. Inhibitors were further prioritized for their potency against other fungal pathogens, and their ability to kill preformed biofilms. Our studies identified the bis-biguanide Alexidine dihydrochloride (AXD), as a drug with the highest antifungal and anti-biofilm activity against a diverse range of fungal pathogens. Finally, AXD significantly potentiated the efficacy of fluconazole against biofilms, displayed low mammalian cell toxicity, and eradicated biofilms growing in mice central venous catheters in vivo, highlighting its potential as a pan-antifungal drug.