Histone deacetylase 6 (HDAC6) is a promising therapeutic target for the treatment of neurodegenerative disorders. SW-100 (<b>1a</b>), a phenylhydroxamate-based HDAC6 inhibitor (HDAC6i) bearing a tetrahydroquinoline (THQ) capping group, is a highly potent and selective HDAC6i that was shown to be effective in mouse models of Fragile X syndrome and Charcot-Marie-Tooth disease type 2A (CMT2A). In this study, we report the discovery of a new THQ-capped HDAC6i, termed SW-101 (<b>1s</b>), that possesses excellent HDAC6 potency and selectivity, together with markedly improved metabolic stability and druglike properties compared to SW-100 (<b>1a</b>). X-ray crystallography data reveal the molecular basis of HDAC6 inhibition by SW-101 (<b>1s</b>). Importantly, we demonstrate that SW-101 (<b>1s</b>) treatment elevates the impaired level of acetylated α-tubulin in the distal sciatic nerve, counteracts progressive motor dysfunction, and ameliorates neuropathic symptoms in a CMT2A mouse model bearing mutant <i>MFN</i>2. Taken together, these results bode well for the further development of SW-101 (<b>1s</b>) as a disease-modifying HDAC6i.