Chemoresistance is a central cause for the tumor management failure. Cancer cells disrupt the redox homeostasis through reactive oxygen species (ROS) regulatory mechanisms, leading to tumor progression and chemoresistance. The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) is a master regulator of neutralizing cellular ROS and restoring redox balance. Understanding the role of NRF2 in ROS-mediated chemoresistance can be helpful in the development of chemotherapy strategies with better efficiency. In this review, we sum up the roles of ROS in the development of chemoresistance to classical chemotherapy agents including cisplatin, 5-fluorouracil, gemcitabine, oxaliplatin, paclitaxel, and doxorubicin, and how to overcome ROS-mediated tumor chemoresistance by targeting NRF2. Finally, we propose that targeting NRF2 might be a promising strategy to resist ROS-driven chemoresistance and acquire better efficacy in cancer treatment.