Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative diseases today. Oxidative stress has been proposed as a key pathological feature in AD. Previous studies in our laboratory show that administration of peptide hormone amylin in mouse models of AD improves cognitive function and reduces oxidative stress damage to membranes. However, how amylin provides neuroprotection against oxidative stress damage is not known. To address this question we treated APP/PS1 mice, a mouse model of AD, with amylin for two months and also treated primary hippocampal neurons from these mice with various doses of amylin. From these treatments, we determined the levels of various oxidative enzymes and stress signaling proteins known to be altered in the AD brain and important in the regulation of oxidative stress damage. Our data shows that, in vitro, amylin is able to dose-dependently protect primary hippocampal neurons from oxidative insults (H2O2). Further, in vivo, a two month treatment with amylin is able to reduce AD-associated upregulation of the Heme-oxygenase-1 (HO-1), an enzyme known to be activated in response to high levels of oxidative stress. Importantly, these reductions in HO-1 paralleled upregulations of MnSOD expression, a classic endogenous antioxidant enzyme, and reductions in levels of phosphorylated JNK, known to be increased during cellular stress. Taken together our data demonstrates that amylin may be improving CNS function through its ability to reduce oxidative stress damage, both by upregulating endogenous protective systems and preventing the activation of cellular cascades.