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Prions are deadly infectious agents made of PrP Sc , a misfolded variant of the cellular prion protein (PrP C ) which self-propagates by inducing misfolding of native PrP C . PrP Sc can adopt different pathogenic conformations (prion strains), which can be resistant to potential drugs, or acquire drug resistance, hampering the development of effective therapies. We identified Zn(II)-BnPyP, a tetracationic porphyrin that binds to distinct domains of native PrP C , eliciting a dual anti-prion effect. Zn(II)-BnPyP binding to a C-terminal pocket destabilizes the native PrP C fold, hindering conversion to PrP Sc ; Zn(II)-BnPyP binding to the flexible N-terminal tail disrupts N- to C-terminal interactions, triggering PrP C endocytosis and lysosomal degradation, thus reducing the substrate for PrP Sc generation. Zn(II)-BnPyP inhibits propagation of different prion strains in vitro , in neuronal cells and organotypic brain cultures. These results identify a PrP C -targeting compound with an unprecedented dual mechanism of action which might be exploited to achieve anti-prion effects without engendering drug resistance., Competing Interests: J.C. and H.E., as part of the company ATLAS Molecular Pharma S.L., declare that they have no conflicts of interest, as the company had no role in study design or funding, nor will they, or their immediate family members, benefit financially from the findings reported. All the other authors declare no competing interests., (© 2023 The Author(s).)