In the present study, we found that carboxymethyl chitosan (CM-Chitosan) and carboxymethyl chitooligosaccharide (CMCOS) induced expression of phase II enzymes such as quinone reductase (QR) in hepatoma (HepG2) cell line. CM-Chitosan and CM-COS had significantly induce QR activity in cultured HepG2 cell. In addition, RNA extract and complementary DNA (cDNA) synthesis by polymerase chain reaction (PCR) from HepG2 cell treated CM-Chitosan and CM-COS. The highest concentration was increased to 200 μg/mL in a concentration-dependent manner the NQO1 (NAD(P)H dehydrogenase (quinone) 1) expression. We also found that CM-COS increased the NQO1, also known as QR mRNA levels through antioxidant response element (ARE) activation as well as Nrf2 (NF-E2 p45-related factor 2) nuclear translocation. The CM-Chitosan and CM-COS found to be functional inducers for QR activation could be good candidates for potential hepatoprotection agents through the regulation of QR.