Oxaliplatin is one of the most common chemotherapy drugs for colorectal cancer (CRC), but its application is greatly limited owing to the drug resistance. Nobiletin is a natural flavonoid isolated from citrus peel and has many biological functions, including anti-inflammatory, antitumor and neuroprotective activities. However, little is known about the effect of nobiletin on the anti-tumor activities of other chemotherapy drugs. In this study, we examined the effect of nobiletin on the efficacy of oxaliplatin in treatment of CRC by using two CRC cell lines. In vitro experiments indicated that nobiletin enhanced the inhibitory effect of oxaliplatin on the proliferation of CRC cells. Meanwhile, nobiletin promoted oxaliplatin-induced apoptosis of CRC cells, as demonstrated by the increased expression of pro-apoptotic proteins (Bax and cleaved-caspse3) and the down-regulation of anti-apoptotic protein Bcl-2. Mechanically, nobiletin sensitized CRC to oxaliplatin chemotherapy by down-regulating the PI3K/Akt/mTOR pathway. Taken together, our study has demonstrated that nobiletin could enhance the sensitivity of CRC to oxaliplatin chemotherapy, and provided a molecular basis for nobiletin’s potential applications in the chemosensitization of CRC.