Sandhoff disease (SD) is a fatal neurodegenerative disorder caused by the absence of β-N-acetylhexosaminidase (Hex) and subsequent accumulation of GM2 ganglioside in lysosomes. Previous studies have led to the development of an adeno-associated virus (AAV) vector-delivered gene therapy for children with GM2 gangliosidosis in both expanded access and phase 1/2 clinical trials through intrathalamic and cerebrospinal fluid-based delivery. This study investigated intravenous delivery of a bicistronic AAV vector-based gene therapy that has not yet been tested in clinical trials to a feline model of SD, treated presymptomatically at 1 month of age. Whereas untreated SD cats lived to 4.3 ± 0.2 months, SD cats treated with low or high doses of the gene therapy lived to 8.3 ± 1.2 or 12.4 ± 2.7 months, respectively. In-life assessments revealed a clinical benefit of AAV treatment, with marked improvements seen in the prevention of overt full-body tremors; cerebrospinal fluid and serum markers of central nervous system damage were also reduced. Magnetic resonance imaging and spectroscopy indicated that the structural pathology and metabolite abnormalities seen in untreated SD cats were partially normalized by treatment. Ultrasound elastography showed improvement in the livers of cats in the high-dose treatment group. Dose-dependent reductions of GM2 ganglioside storage and increases in Hex activity were documented, associated with reduced neuroinflammatory cell populations and partial correction of myelin deficits. These data support the dose-dependent efficacy of intravenous-delivered gene therapy for restoration of Hex activity and preservation of clinical metrics, supporting potential for translation to patients with SD.