Tau is a microtubule-associated protein that plays an important role in the assembly and stabilization of microtubules. Aggregated tau is a key characteristic of tauopathies such as Alzheimer's disease, corticobasal degeneration, progressive supranuclear palsy, and Pick's disease. Accumulation of abnormal tau causes neuronal and synapse damage, microtubule destabilization, and neuroinflammation, leading to cognitive decline and motor dysfunction. Histone deacetylase 6 (HDAC6) regulates α-tubulin, HSP90, and tau acetylation within the cytoplasm, and can promote tau aggregation. Inhibiting of HDAC6 is involved in degrading tau through the tau clearance pathways, namely the ubiquitin-proteasome system and autophagy-lysosome system. Here, we investigated the effect of HPOB, an HDAC6 inhibitor, on hyperphosphorylated tau in vitro and in vivo. HPOB significantly increased the acetylation of α-tubulin and decreased the interaction of HDAC6 and heat shock protein 90 without cytotoxicity in the tau (P301L) expressing SH-SY5Y cells. HPOB also markedly reduced the protein expression of Ser262, Thr231, and AT8 via increasing autophagy-lysosome system. In addition, we administered HPOB to 6-month-old PS19 mice for 2 months to examine effect of HPOB on spatial memory deficits. HPOB-treated PS19 mice were ameliorated spatial memory dysfunction. Overall, this suggests that HPOB may be a promising therapeutic to alleviate tauopathies by reducing hyperphosphorylated tau.