Heavy metal-induced neuroinflammation is a significant pathophysiologic mechanism in Alzheimer's disease (AD). Microglia-mediated neuroinflammation plays a crucial role in the pathogenesis of AD. Multiple miRNAs are differentially expressed in peripheral tissues after heavy metal exposure, and increasing evidence suggests that they are involved in AD progression by regulating microglial homeostasis. Exosomes, which are capable of loading miRNAs and crossing the blood-brain barrier, serve as mediators of communication between peripheral tissues and the brain. In this review, we summarize the current evidence on the link between miRNAs in peripheral tissues and neuroinflammation in AD after heavy metal exposure and propose a role for miRNAs in the microglial neurodegenerative phenotype (MGnD) of AD. This study will help to elucidate the link between peripheral tissue damage and MGnD-mediated neuroinflammation in AD after heavy metal exposure. Additionally, we summarize the regulatory effects of natural compounds on peripheral tissue-derived miRNAs, which could be potential therapeutic targets for natural compounds to regulate peripheral tissue-derived exosomal miRNAs to ameliorate heavy metal-induced MGnD-mediated neuroinflammation in patients with AD after heavy metal exposure.