Contactin-associated protein-like 2 (CNTNAP2) gene, located on chromosome 7q35, is one of the largest genes in the human genome. CNTNAP2 protein is a type-I transmembrane protein specifically expressed in the nervous system, with versatile roles in the axonal organization, synaptic functions, neuronal migration, and functional connectivity. CNTNAP2 has been widely investigated as a risk gene for autism spectrum disorder (ASD), and recent studies also implicated CNTNAP2 in Alzheimer’s disease (AD). Knowledge of the regulations on CNTNAP2’s life cycle is necessary for understanding the related physiological functions and pathological conditions. However, the mechanisms underlying CNTNAP2 protein degradation remain elusive. Therefore, we systematically investigated the half-life and degradation pathway of the human CNTNAP2 protein. We discovered that CNTNAP2 has C-terminal fragments (CTF), which may have essential physiological functions. Our results demonstrated that CNTNAP2 full-length protein and CTF have a short half-life of about 3–4 h. CNTNAP2 proteins are degraded by the ubiquitin–proteasome system and the macroautophagy-lysosome pathway, while the lysosome pathway is more common for CNTNAP2 degradation. This study will provide novel insights and valuable tools for CNTNAP2 functional research in physiological and pathological scenarios.