<p>Prion diseases are neurodegenerative disorders that affect both humans and animals. They are commonly characterized by the absence of DNA and RNA and are distinguished from inherited or infectious forms. The cellular prion proteins (PrP^C) misfold and accumulate into their pathogenic isoforms in these diseases. Disease conditions like Gerstmann-Straussler-Scheinker disease, Creutzfeldt-Jakob disease, and fatal familial insomnia are all related to prion proteins. The majority of the patients with prion disorders have a life expectancy of less than a year. An effective therapeutic approach for these prion diseases remains a formidable challenge. This review focuses on novel therapeutic approaches, such as antibody-based treatments that aim to stop normal proteins from changing into the harmful form of the prion protein (PrP^Sc). Additionally, the review discusses the potential of RNA interference, antisense oligonucleotides, anti-aggregation compounds, β-sheet breakers, and stem cell-based therapies in addressing prion diseases.</p> Graphical abstract <p></p>