Inhibition of histone deacetylase 6 (HDAC6) in the brain is a highly attractive therapeutic target for the treatment of neurodegenerative diseases. The low blood-brain barrier permeability of most known HDAC6 inhibitors, however, prevents their application as central nervous system (CNS) drugs. To overcome this problem, we designed and synthesized benzylpiperazine derivatives using a hybrid strategy of combining HDAC6 inhibitors and brain-penetrant histamine H<sub>1</sub> receptor antagonists. Introducing the benzylpiperazine units to the cap region of hydroxamate-type HDAC6 inhibitors led us to identify isozyme-selective and CNS-penetrant HDAC6 inhibitor KH-259 (<b>1</b>) with the appropriate pharmacokinetic and safety properties. Intraperitoneal administration of KH-259 (10 mg/kg) had antidepressant activity and increased acetylated α-tubulin in the brain without promoting acetylated histone H3K9. These findings indicate that our hybrid strategy of combining HDAC6 inhibitors and histamine H<sub>1</sub> receptor antagonists is an effective methodology for designing CNS-penetrant HDAC6 inhibitors.