Recently, a variant of insulin‐like growth factor‐1, mechano‐growth factor (MGF), has been discovered whose 24‐amino‐acid carboxy end is protective in models of stroke, nerve injury, and amyotrophic lateral sclerosis, suggesting broad‐spectrum neuroprotective properties. Moreover, we recently demonstrated in vitro and in vivo that a modified protease‐resistant 24‐amino‐acid MGF derivative (MGF24) protects dopaminergic neurons from oxidative stress‐induced apoptosis via induction of the stress response protein heme oxygenase‐1. However, the underlying mechanism by which MGF24 up‐regulates heme oxygenase‐1 expression is unknown. In this study, we demonstrate that MGF24‐induced heme oxygenase‐1 up‐regulation is dependent on activation of protein kinase Cϵ and NF‐E2‐related factor‐2 (Nrf2). MGF24 induces nuclear translocation of Nrf2, and siRNA knockdown of Nrf2 or of heme oxygenase‐1 prevents MGF24‐induced heme oxygenase‐1 up‐regulation and neuroprotection of SH‐SY5Y cells against 6‐hydroxydopamine‐induced cell death. Pharmacological inhibition of ERK, p38 MAPK, PI3K/Akt, or PKC signaling revealed that only PKC inhibition by GF109203X prevents MGF24's ability to protect against 6‐hydroxydopamine‐induced cell death. GF109203X also prevented MGF24‐induced Nrf2 nuclear translocation and heme oxygenase‐1 up‐regulation. siRNA knockdown of protein kinase Cϵ blocks MGF24‐induced Nfr2 nuclear translocation, heme oxygenase‐1 expression, and neuroprotection. Taken together, these results demonstrate that PKC activity is needed for MGF24's activation of Nrf2, which in turn increases heme oxygenase‐1 expression, a critical event in mediating MGF24's neuroprotection against 6‐hydroxydopamine‐induced apoptosis. Published 2011 Wiley‐Liss, Inc.