Neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) frequently co-occur, yet their shared and distinct molecular mechanisms remain poorly understood. Here, we performed proteomic analysis to investigate the molecular signatures of ASD, ADHD, and their comorbid condition (ASD+ADHD) from exosome. We identified both disorder-specific and trans-diagnostic protein biomarkers, including CLTB and CLINT1 for ASD and ASD+ADHD, respectively, as well as shared dysregulation of IGHV1-18, KRT86, KIF5B and STXBP5 across all three conditions. Pathway analysis revealed widespread dysregulation of proteins associated with the collagen-containing extracellular matrix and extracellular region across all three disorders, and also identified disorder specific mechanism, including clathrin-mediated synaptic endocytosis abnormalities and lipid metabolism dysregulation in ASD, dynactin complex dysfunction in ADHD, and unique perturbations in integrin signaling and chemokine pathways for comorbid condition. Notably, ASD+ADHD exhibited both additive and unique molecular features, and showed higher similarity with ADHD-only group. Machine learning-based predictive modeling demonstrated the diagnostic potential of our protein panels, achieving AUCs of 0.77–0.88 in distinguishing disorders from controls and from each other. Our findings provide new insights into the pathophysiology of these disorders and highlight potential biomarkers for improved diagnosis and subtyping.