Neuronal ceroid lipofuscinoses (NCLs), commonly known as Batten disease, are a group of rare, inherited neurodegenerative disorders caused by pathogenic variants in one of 13 NCL genes. Despite decades of intensive research, the molecular function of many of the NCL proteins remains elusive. Additionally, the biological processes affected by disease are poorly understood, which has prevented the identification of disease specific biomarkers. Here, we conducted a comprehensive longitudinal analysis of lipid, metabolite, and protein changes at early- and late-stage disease in large animal models of CLN1, CLN2, CLN3, CLN5, and CLN6 disease. Metabolomics and lipidomic assessments were performed using four separate chromatograph-Mass spectrometry (LC-MS) workflows, while proteomics was assessed using a novel deep-multi nanoparticles (NPs) corona-based proteomics workflow for deep plasma proteomics. Taken together, these data help to elucidate unique and shared pathways that are perturbed in multiple NCLs. Additionally, these data provide the framework for a novel “biomarker panel” with the potential for improved disease diagnosis, tracking, and evaluation of therapeutic efficacy across multiple NCLs.