Alzheimer’s disease (AD) involves amyloid accumulation, neuroinflammation, oxidative stress, and cognitive decline. AMP-activated protein kinase (AMPK) regulates energy homeostasis and neuronal function, but most AMPK activators act indirectly by inducing metabolic stress. We previously identified YE-06 as a CBS3-targeting direct AMPK activator through virtual screening, structure–activity relationship analysis, computer-aided scaffold design, and structural optimization. Transcriptomic analysis of human hippocampal tissues revealed suppression of AMPK-associated signaling networks in AD. Molecular docking predicted that YE-06 binds the CBS3 site of AMPKγ through H298 and R299, while cellular thermal shift assays confirmed direct engagement dependent on these residues. YE-06 activated AMPK in neuronal and microglial cells and sustained its activation through an LKB1-dependent mechanism. It suppressed BACE1 expression and amyloidogenic APP processing through the AMPK–SIRT1–NF-κB axis and reduced inflammation and oxidative stress by inhibiting NF-κB and activating Nrf2. YE-06 improved cognitive function and neuronal outcomes in vivo models. YE-06 also showed 76.0% oral bioavailability, brain exposure, and a preliminary safety profile. These findings support direct AMPK activation by YE-06 as a potential disease-modifying strategy for AD.