Prion diseases are characterised by severe neural lesions linked to the presence of an abnormal protease‐resistant isoform of cellular prion protein (PrPc). The peptide PrP(106–126) is widely used as a model of neurotoxicity in prion diseases. Here, we examine in detail the intracellular signalling cascades induced by PrP(106–126) in cortical neurons and the participation of PrPc. We show that PrP(106–126) induces the activation of subsets of intracellular kinases (e.g., ERK1/2), early growth response 1 synthesis and induces caspase‐3 activity, all of which are mediated by nicotinamide adenine dinucleotide phosphate hydrogen‐oxidase activity and oxidative stress. However, cells lacking PrPc are similarly affected after peptide exposure, and this questions the involvement of PrPc in these effects.