Colorectal cancer (CRC) is the fourth leading cause of cancer−related death worldwide. Activation of ABCB1 gene and its main product, P−glycoprotein, is the common reason for chemoresistance. The nuclear factor–erythroid 2–related factor2 (Nrf2) is directly regulated by Kelch like ECH–associated protein1 (Keap1). In addition, Nrf2 is a key transcriptional factor that regulates efflux transporters, including P−gp. The aim of this study was to investigate the expression levels of Nrf2, Keap1 and ABCB1 in the biopsy samples and their association with clinicopathological features in CRC patients. Both mRNA and protein expression levels were measured by Real−time PCR and immunohistochemistry (IHC), respectively, in biopsies from colonoscopy in 65 CRC patients compared to those in 65 non−CRC individuals. While expression levels of Nrf2 and ABCB1 (P−gp) were markedly higher in both mRNA and protein levels in CRC biopsies (p < 0.01), Keap1 expression level was significantly lower in these samples (p < 0.05). Positive correlations between Nrf2 expression level and tumor size (p = 0.003), lymph node (p = 0.038), distant metastasis (p = 0.008), and smoking status (p = 0.02) were observed. However, P–gp expression was associated only with patient age and smoking status. In addition, there was a positive correlation between protein levels of Nrf2 and P−gp, in both CRC (r = 0.617, p < 0.001) and non−CRC tissues (r = 0.930, p < 0.001). In conclusion, over-expression of Nrf2 and ABCB1/P−gp, as well as down-regulation of mRNA expression level of Keap1 in CRC patients denotes the role of Keap1/Nrf2/ABCB1 axis in CRC progression and chemoresistance. Our data suggest that therapeutic inhibition of Nrf2/ABCB1 signaling can be considered as a novel strategy to improve the efficacy of chemotherapeutics against CRC.