Structure‐based discovery of small molecule histone deacetylase 6 (HDAC6) inhibitor PB118 shows multi‐modal mechanisms of action that lead to the attenuation of Alzheimer's disease (AD) neuropathology through clearing amyloid debris by phagocytosis, stabilizing microtubule network by elevating the expression of acetylated‐α‐tubulin, and significantly reducing tau phosphorylation and neuroinflammation. Here, MAPT is linked to Alzheimer disease.