CLN2 Batten Disease is a rare neurodegenerative disorder caused by mutations in the lysosomal enzyme TPP1. Current biomarkers for this disease, such as neurofilament light (NfL), lack specificity to CLN2 disease and may not capture any non-neuronal impacts of the disease. A more thorough understanding of changes in blood biomolecules in individuals with CLN2 Batten Disease would give a more targeted understanding of core disease mechanisms. Moreover, these changes can be used as biomarkers for more refined clinical assessment and early disease detection. Here we use blood drawn from CLN2 Batten Disease patients and CLN2R208X Yucatan miniature pigs for discovery and validation of novel disease biomarkers. We first performed proteomic and metabolomic analysis in blood samples from the pig model of CLN2 batten disease at multiple timepoints. We found over 250 altered metabolites and over 700 altered proteins in our analysis of 18-month-old animals. The most profound changes we observed were accumulations of acylcarnitine species in CLN2 Batten Disease pigs. This is supported by direct metabolite analysis of CLN2 Batten Disease patient blood samples which also showed altered levels of acylcarnitines. These fatty esters are substrates for beta-oxidation pathways and their accumulation is linked to mitochondrial dysfunction, ultimately leading to impaired metabolism and excess reactive oxygen species. Moreover, their accumulation suggests a broader metabolic stress could be an important aspect of the disease, which would not be exclusive to the CNS. To test whether other metabolically demanding cells are affected, we analyzed a panel of protein biomarkers associated with cardiovascular dysfunction, finding elevated markers of heart failure and cardiomyopathy in 18-month-old CLN2 pigs. These findings suggest a more widespread impact of CLN2 Batten Disease, affecting peripheral tissues and tied to metabolic dysfunction.