Prion diseases are a group of neurodegenerative disorders characterized by the accumulation of misfolded prion protein (called PrP<sup>Sc</sup>). Although conversion of the cellular prion protein (PrP<sup>C</sup>) to PrP<sup>Sc</sup> is still not completely understood, most of the therapies developed until now are based on blocking this process. Here, we propose a new drug strategy aimed at clearing prions without any direct interaction with neither PrP<sup>C</sup> nor PrP<sup>Sc</sup>. Starting from the recent discovery of SERPINA3/SerpinA3n upregulation during prion diseases, we have identified a small molecule, named compound 5 (ARN1468), inhibiting the function of these serpins and effectively reducing prion load in chronically infected cells. Although the low bioavailability of this compound does not allow <i>in vivo</i> studies in prion-infected mice, our strategy emerges as a novel and effective approach to the treatment of prion disease.