Development of de novo therapeutic agents is a complex, costly, and a high-risk process, whereas repurposing approved and investigational drugs for novel targets offers a more efficient and cost-effective strategy, likely yielding higher success rates. This approach demonstrated its effectiveness during SARS-CoV-2 pandemic, when existing drugs were repurposed to combat the virus. Originally pivotal in developing antiviral treatments against HIV and HCV, viral protease inhibitors represent a structurally privileged class of compounds capable of targeting difficult and non-classical protein sites. They have demonstrated promising biological activity against diverse alternative targets, including fungal pathogens, multidrug-resistant bacteria, and cancer, making them prime candidates for repurposing. This mini-review highlights the unique structural and physicochemical properties of approved HCV and HIV viral protease inhibitors that enable their repurposing for the development of new therapeutic agents.