Background: The well-being of disaster responders is just as important as that of disaster victims as maintaining responders’ health is essential for the effective disaster response. This study aimed to identify the key factors contributing to fatigue in disaster responders. Methods: This cross-sectional study analyzed data from disaster responders deployed during the 2024 Noto Peninsula Earthquake in Ishikawa prefecture, Japan. Data were collected using the health management version of the Japanese Surveillance in Post-Extreme Emergencies and Disasters app from January to March 2024. Associations between contributing factors including problems in the work environment, type of work activity, and occupation, and self-reported fatigue score were examined using the t-tests, analysis of variance, and multivariable regression analysis. Results: We analyzed 15,067 data entries from disaster responders. Fatigue levels among disaster responders were generally low, with 73.7% of scores between 1 and 3 during the first phase and 82.3% during the second phase. Fatigue was significantly higher in the early response phase (β = 0.32, 95% confidence interval [CI]: 0.27—0.37) and among logisticians (β = 0.23, 95% CI: 0.18—0.28) and Health Emergency Operations Center staff (β = 0.20, 95% CI: 0.14—0.25) than among nonlogisticians and non —Health Emergency Operations Center staff members. Problems in the work environment had the largest effects: inability to take meals and breaks increased fatigue by 1.82 points (95% CI: 1.56—2.07), and unclear tasks or command structures by 0.82 points (95% CI: 0.57—1.06). Conclusion This study underscores the importance of establishing a structured command system, strengthening responder training and improving working conditions to safeguard responder well-being.