Cancers in the upper aerodigestive tract, including cancers of the tongue and the esophagus, are the third leading cause of cancer-related deaths in the world, and oxidative stress is well recognized as one of the major risk factors for carcinogenesis. The Keap1-Nrf2 system plays a critical role in cellular defense against oxidative stress, but little is known about its association with upper aerodigestive tract carcinogenesis. In this study, we examined whether loss of Nrf2-function exacerbates carcinogenesis by using an experimental carcinogenesis model that is induced by 4-nitroquinoline-1-oxide (4NQO). We found that Nrf2-knockout (Nrf2-KO) mice were more susceptible to 4NQO-induced tongue and esophageal carcinogenesis than wild-type mice, which suggests that Nrf2 is important for cancer prevention. We also examined how the suppression of Keap1 function or the induction of Nrf2 activity affected 4NQO carcinogenesis. Keap1-knockdown (Keap1-KD) mice were resistant to 4NQO-induced tongue and esophageal carcinogenesis. Importantly, no growth advantage was observed in tongue tumors in the Keap1-KD mice. These results show that the Keap1-Nrf2 system regulates an important defense mechanism against upper aerodigestive tract carcinogenesis. In addition to several important functions of Nrf2 that lead to cancer chemoprevention, we hypothesize that a mechanical defense of thickened keratin layers may also be a chemopreventive factor because thickened, stratified, squamous epithelium was found on the tongue of Keap1-KD mice.