ApoE-mimetic peptides gained significant attention for their therapeutic potential for various pathophysiological conditions. Apolipoprotein E (ApoE) is a central protein involved in lipid transport, metabolism, and neuronal repair. Dysfunction in the ApoE has been associated with various diseases, viz., Alzheimer’s, cardiovascular disorders, and certain metabolic syndromes. ApoE-mimetic peptides are small synthetic peptides that emulate the structural and biological properties of the native ApoE and offer a targeted approach to alleviate these diseases by enhancing lipid homeostasis, reducing inflammation, and providing neuroprotection. This chapter explores the therapeutic potential of ApoE-mimetic peptides for different ailments, highlighting the preclinical and clinical studies demonstrating their therapeutic benefits, and discusses potential challenges and future directions in their development as novel treatment modalities. Moreover, the use of ApoE-mimetic peptides as a carrier for delivering various drugs to CNS is also discussed along with the possible therapeutic benefits of ApoE-mimetic peptides in improving disease outcomes and advancing personalized medicine approaches.