CLN2 disease is one of the most common forms of NCL and caused by inherited mutations in the lysosomal protease tripeptidyl peptidase 1 (TPP1). Until recently, most therapeutic efforts have understandably focused on the CNS. Although these largely treat or prevent pathological changes in the brain and their fatal seizure phenotype, Tpp1R207X/R207X mice still die prematurely, suggesting the existence of significant life-limiting effects of disease outside the CNS. Our work has highlighted a severe impact of TPP1 deficiency upon the enteric nervous system (ENS), causing the loss of many enteric neurons and bowel dysmotility. This ENS disease can be treated by intravenous (IV) gene therapy with AAV9-hTPP1, but this approach does not effectively treat the CNS, especially if delivered postweaning as the AAV9 vector doesn’t reach the brain due to blood brain barrier maturation. We first tested whether CNS directed therapies could also treat ENS disease in Tpp1R207X/R207X mice. Our analyses revealed that CNS directed enzyme replacement (ERT) and gene therapy administrated intraventricularly (ICV) are effective upon disease in the brain, where we observed significant reduction in accumulation of storage material and glia activity in vulnerable brain regions. However, these same CNS-directed therapies did not prevent degeneration in the ENS. To optimize therapeutic outcomes, we combined neonatal ICV delivery of AAV9-hCLN2 to treat the CNS, with neonatal IV gene therapy to treat ENS disease. Our analyses of these mice showed protective effects in both the CNS and ENS, largely preventing pathology in both the brain and bowel, significantly extending the lifespan of these mice. Taken together, our results suggest that more complete treatment effects for CLN2 disease can be achieved by simultaneously targeting both the CNS and ENS. These data have implications for treating other forms of NCL via similar strategies.