Caloric restriction (CR), which improves health and increases longevity, was studied as a therapy in a hexosaminidase β knockout mouse model of Sandhoff disease (SD), an incurable neurodegenerative disease involving accumulation of brain ganglioside GM2 and asialo-GM2 (GA2). Adult mice were fed a rodent chow diet either ad libitum (AL) or restricted to reduce body weight by 15–18% (CR). Although GM2 and GA2 were elevated, no significant differences were seen between the Hexb−/− and the Hexb+/− mice for most brain phospholipids and cholesterol. Cerebrosides and sulfatides were reduced in the Hexb−/− mice. In addition, rotorod performance was significantly worse in the Hexb−/− mice than in the Hexb+/− mice. CR, which decreased circulating glucose and elevated ketone bodies, significantly improved rotorod performance and extended longevity in the Hexb−/− mice but had no significant effect on brain lipid composition or on cytoplasmic neuronal vacuoles. The expression of CD68 and F4/80 was significantly less in the CR-fed than in the AL-fed Hexb−/− mice. We suggest that the CR delays disease progression in SD and possibly in other ganglioside storage diseases through anti-inflammatory mechanisms.