Based on reports, Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase 2 (PLOD2) constitutes an oncogenic gene that undergoes upregulation in multiple malignancies, encompassing cervical cancer, endometrial cancer, and lung cancer. PLOD2 is competent to stiffen the extracellular matrix and modify the ECM architecture. Despite the fact that PLOD2 has been demonstrated to be associated with an unfavorable prognosis in colorectal cancer (CRC), the regulatory mechanism and functionality of PLOD2 in human colorectal cancer remain enigmatic. In this investigation, we validated the elevated expression of PLOD2 in human CRC tissue and its correlation with tumor pathological staging. Concurrently, we discerned through public databases that the expression of PLOD2 is interrelated with patient prognosis. Furthermore, functional experiments have manifested that PLOD2 facilitates CRC cell metastasis and proliferation via the PI3K-AKT pathway and predicts the potential binding of compounds to its protein.