Neuroinflammation and microglial activation are common features in Alzheimer’s disease (AD) and excessive alcohol consumption. Alcohol induces liver damage and inflammation, and altered serum aminotransferases have been reported in patients with AD. Small extracellular vesicles (sEVs) and their cargo are emerging as mediators of intercellular communication in AD and alcohol-induced liver injury. However, the effects of alcohol use on AD progression remain to be elucidated. In this study, we evaluated the effects of repeated binge drinking on the liver and brain in the APP/PS1 mouse model of AD. Alcohol-exposed APP/PS1 mice showed elevated serum alanine aminotransferase levels, indicating liver injury absent in controls, along with increased pro-inflammatory cytokine expression in both liver and brain. Alcohol increased the biogenesis and release of sEVs in AD mice and in mouse hepatocytes. These sEVs were enriched in mature miR-122-5p that is predominant in hepatocytes. In vivo, miR-122-5p was detected in the brain of alcohol-exposed AD mice suggesting EV-mediated miR-122-5p transfer to the brain. Microglial uptake of hepatocyte-derived sEVs was confirmed in vitro. sEVs from alcohol-treated hepatocytes sensitized BV-2 microglia to LPS stimulation, significantly enhancing CCL2, CXCL2, CCL3, and TNF-α production. Transfection of microglia with a miR-122-5p mimic partially recapitulated the pro-inflammatory sensitization by sEVs from alcohol-exposed hepatocytes, which was reversed by miR-122-5p inhibitor delivery. ADAM10, a miR-122-5p target, was reduced in both wild-type and AD brains after alcohol exposure, with cell-specific effects. These results suggest that alcohol-induced hepatocyte-derived sEVs may modulate liver-to-brain signaling via miR-122-5p and contribute to neuroinflammation in AD.