AbstractResistance to chemotherapy is the deadlock in cancer treatment. In this study, we used wild‐type LOVO (LOVOWT), a human colon cancer cell line, and the oxaliplatin‐resistant sub‐clone LOVOOR cells to investigate the molecular mechanisms of the development of drug resistance in colon cancer. Compared with LOVOWT cells, LOVOOR cells had a high proliferation capacity and a high percentage on the G2/M phase. The expression and activation of Aurora‐A, a critical kinase in G2/M phase, were higher in LOVOOR cells than in LOVOWT cells. The results from immunofluorescence indicated an irregular distribution of Aurora‐A in LOVOOR cells. To evaluate the importance of Aurora‐A in oxaliplatin‐resistant property of LOVOOR cells, overexpression of Aurora‐A in LOVOWT cells and otherwise knockdown of Aurora‐A in LOVOOR cells were performed and followed by administration of oxaliplatin. The results indicated that Aurora‐A might contribute to the resistance of LOVOOR cells to oxaliplatin treatment by depressing p53 signaling. The specific findings in this study provide a possibility that targeting Aurora‐A might be a solution for patients who have failed oxaliplatin treatment.