Altered glucose uptake and metabolism is the key characteristic of cancer cells including hepatocellular carcinoma (HCC). However, role of glucose availability in chemotherapeutic outcome of HCC is unclear. The present study investigates the effect of glucose facilitated sensitization of HCC cells towards doxorubicin (DOX) and sorafenib (SORA). In HCC cells, we observed that hyperglycemic culture condition (HG) is associated with increased sensitivity towards DOX and SORA. P-glycoprotein (P-gp), a transporter involved in drug efflux, was elevated in HCC cells in NG, rendering them less susceptible to DOX and SORA. Further, this study demonstrated that knockdown of dickkopf protein 4 (DKK4), a Wnt antagonist protein, causes enhanced glucose uptake and reduction in P-gp level rendering HCC cells in NG sensitive to DOX and SORA. Moreover, HG elevates the level of intracellular reactive oxygen species (ROS), which regulates P-gp. Alteration in intracellular ROS did not directly affect regulation of DKK4 in HCC cells. Functional assays suggest that alterations in DKK4 and P-gp level in HCC cells are dependent on glucose availability and changes in ROS level because of enhanced glucose utilization, respectively. Collectively, the present study highlights direct involvement of glucose-induced ROS, DKK4 and P-gp in altering the sensitivity of HCC cells towards DOX and SORA.