Alzheimer’s disease (AD) is a neurodegenerative disorder with increasing prevalence and lack of effective treatments highlighting the urgent need to develop novel therapeutic strategies. Scutellaria baicalensis, a traditional Chinese medicinal herb, exhibits anti-inflammatory, antioxidant, and neuroprotective effects against AD. However, the therapeutic potential of its extracellular vesicles (Sb-EVs) remains unexplored. In this study, the effects and underlying mechanisms of Sb-EVs on AD via different administration routes are systematically investigated. The intravenous (i.v.) injection of Sb-EVs effectively crosses the blood-brain barrier (BBB), significantly inhibiting neuronal apoptosis by clearing amyloid-beta (Aβ)—induced intracellular reactive oxygen species (ROS) and repairing mitochondrial damage. In contrast, orally administered Sb-EVs is limited by lower brain-targeting efficiency. It improves AD phenotypes via the gut-brain axis by remodeling gut microbiota and modulating metabolic levels. The i.v.-injected Sb-EVs exhibited superior efficacy to that of oral administration by improving cognitive function and attenuating Aβ deposition. Collectively, the potential of Sb-EVs as high-safety, high-efficacy natural nanomedicines for alleviating AD was elucidated.