Systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) are chronic autoimmune disorders with overlapping clinical features yet distinct pathophysiological pathways. This study aimed to explore disease-specific metabolic alterations using a Nuclear Magnetic Resonance (NMR)-based serum metabolomics approach. A total of 35 metabolites were quantified and analyzed across SSc, SLE, and healthy control (HC) groups using CHENOMX software, with additional focus on three rationally selected metabolite ratios. Multivariate and univariate statistical analyses revealed distinct metabolic disruptions: SLE exhibited pronounced alterations in energy metabolism pathways such as glycolysis and the tricarboxylic acid (TCA) cycle, along with markers of oxidative stress, whereas SSc showed specific disruptions in inositol and amino acid metabolism, particularly involving arginine, proline, and glutamate, alongside indicators of fibrosis and endothelial dysfunction. Acetate emerged as a key discriminatory metabolite, with significantly elevated levels in SSc patients, suggesting enhanced fatty acid oxidation potentially linked to fibrotic progression. Receiver operating characteristic (ROC) curve analyses, including multivariate and multiclass models, demonstrated high diagnostic accuracy for metabolite ratios incorporating acetate, underscoring their utility as potential biomarkers. These findings reveal distinct metabolic fingerprints for SSc and SLE, offering new insights into their underlying mechanisms and supporting the development of metabolomics-based diagnostic and therapeutic strategies.