BACKGROUND: Depression is a major problem among nurses; hence, it is important to develop a primary prevention strategy to manage depression among nurses. This randomized controlled trial (RCT) study aims to investigate the effects of a newly developed internet-based cognitive behavioral therapy (iCBT) program on depressive symptoms, measured at baseline and three- and six-month follow-ups, among nurses in Japan. METHODS: Nurses working at three university hospitals, one public hospital, and twelve private hospitals who meet inclusion criteria will be recruited and randomized either to the intervention group or the control group (planned N = 525 for each group). The newly developed iCBT program for nurses consists of six modules, which cover different components of cognitive behavioral therapy (CBT); transactional stress model (in module 1), self-monitoring skills (in module 2), behavioral activation skills (in module 3), cognitive restructuring skills (in modules 4 and 5), relaxation skills (in module 5), and problem-solving skills (in module 6). Participants in the intervention group will be asked to read these modules within 9 weeks. The primary outcome will be depressive symptoms as assessed by the Beck Depression Inventory-II (BDI-II) at baseline, three-, and six-month follow-ups. DISCUSSION: The greatest strength of this study is that it is the first RCT to test the effectiveness of the iCBT program in improving depressive symptoms among nurses. A major limitation is that all measurements, including major depressive episodes, are self-reported and may be affected by situational factors at work and participants' perceptions. TRIAL REGISTRATION: This trial was registered at the University Hospital Medical Information Network clinical trials registry (UMIN-CTR; ID =  UMIN000033521 ) (Date of registration: August 1, 2018).