Emerging evidence supports that sleep disorders are the main risk factor for sporadic Alzheimer’s disease (AD), and iron dysregulation may be the link between them. Our previous studies have confirmed that ketogenic diet (KD) can prevent chronic sleep deprivation-induced AD. However, it is uncertain whether exogenous ketones supplements (EKS), as an alternative intervention, have the same effects as KD. Thus, we investigated the prophylactic efficiency of EKS on chronic sleep deprivation-induced AD and reveal the underlying mechanism focus on iron metabolism. We observed that the prophylactic efficacy of EKS against chronic sleep deprivation-induced AD was comparable to that of KD. Meanwhile, our results suggest that both EKS and KD inhibited iron metabolism disorder through regulation of iron metabolism-related proteins. Moreover, we found that both EKS and KD reduced hippocampal mitochondrial dysfunction and iron-mediated lipid peroxides. Furthermore, EX527 (silent information regulator 1 (Sirt1) inhibitor), mostly abrogated these above protections of EKS, suggesting that the prophylactic effect of EKS on AD is partly dependent on Sirt1. Our findings provide novel evidence that EKS can be developed as functional foods to prevent or delay the development of AD, particularly in individuals with sleep disorders.