Prion diseases are neurodegenerative disorders characterized by the accumulation of an abnormal isoform of the protease-insensitive isoform (PrPSc) of prion protein. Human prion protein fragment 106‑126 [PrP (106‑126)] contains most of the pathological characteristics associated with PrPSc. Although a number of compounds have been identified to inhibit PrP accumulation or dissolve fibrils and aggregates in vitro, there is currenlty no treatment available for these progressive neurodegenerative diseases. Baicalein, the dried root of Scutellaria baicalensis (S. baicalensis) Georgi (known as Huang-qin in traditional Chinese medicine) has been reported to exert neuroprotective effects on neurodegenerative diseases. In the present study, we investigated the effects of baicalein on the development of prion diseases using SH-SY5Y and SK-N-SH cells in vitro. We found that baicalein protected the cells against PrP‑induced neuronal cell death by inhibiting the production of reactive oxygen species (ROS) and mitochondrial dysfunction using ROS detection assay and MTP assay. We demonstrated that baicalein treatment regulated the phosphorylation of c-Jun N-terminal kinase (JNK) by using western blot analysis and Annexin V assay. Our data suggest that baicalein has potential for use as a therapeutic drug for the treatment of various neurodegenerative diseases, including prion diseases.