Bacterial pathogens possess the remarkable ability to sense and adapt to their constantly changing environments. For example, Vibrio cholerae, the causative agent of the severe diarrheal disease cholera, thrives in aquatic settings and infects human hosts, employing dynamic strategies to ensure survival between diverse environments. In this study, we utilized RNA sequencing to investigate how V. cholerae responds to nitric oxide (NO), a common stressor encountered during infection. We found that cry1, encoding a photolyase, which repairs DNA damage caused by exposure to blue light—a stressor found in aquatic environments—was induced by NO. We observed that cry1 was activated upon exposure to blue light and Cry1 contributed to mitigating blue light-induced reactive oxygen species (ROS) production and stress responses. Cry1 is important for protecting cells against blue light-induced cell death. Furthermore, we showed that pre-induced Cry1 production, either by exposure to reactive nitrogen species (RNS) in vitro or in mice, enhanced V. cholerae’s resistance to blue light. Additionally, we found that V. cholerae Cry1 and the E. coli ortholog PhrB were crucial in resisting reactive oxygen species (ROS). Moreover, cry1 expression was regulated by RpoE and the anti-sigma factor ChrR, with two cysteine residues in ChrR playing vital roles in sensing RNS and blue light-induced ROS, thereby modulating cry1 expression. Collectively, our findings suggest that V. cholerae encounters host-derived NO during infection, and the subsequent induction of Cry1 primes the bacterium effectively for challenges in aquatic environments abundant in blue light once it exits the host gut.