Abstract Introduction Job-related stress and sleep disturbances are common problems among registered nurses (RNs). At present, more than half of the nursing staff in Taiwan have the intention to leave, so this is a problem that cannot be ignored. This cross-sectional correlational research based on Job Demands-Resources Model aimed to explore the influencing factors of work well-being from sleep and job crafting perspective. Methods A total of 220 (13.3% was male) shift-work RNs (mean age= 30.6, SD= 6.5), were recruited from seven intensive care units of a teaching hospital in central Taiwan. All nurses completed a battery questionnaires measuring their job-related stress, sleep disturbances, fatigue severity, self-efficacy, job crafting, and work well-being. In addition, a 7-day sleep diary were collected to estimate their total sleep time (TST). Results Majority of the RNs reported poor sleep quality (61.5%), insufficient sleep quantity (62.8%), and poor daytime functioning (49.5%). According to the sleep diary, their average TST (464 minutes, SD= 91.7) was close to what they needed to feel refreshed (472 minutes, SD= 87.5); however, more than three-quarters of them experienced clinically significant fatigue before bedtime (92.3%) and after waking up (72.7%). Job-related stress was measured by the Copenhagen Psychosocial Questionnaire II, the top three stressors were from value at work level, interpersonal relations and leadership, and work organization. Sleep disturbances was correlated with poor work well-being. After controlling for personal factors (age, gender, and years in nursing) and sleep disturbances, self-efficacy, job-related stress, and job crafting explained 49.8% of work well-being; work organization, value at work level, and job crafting are the significant predictors. Conclusion Most RNs in this study reported sleep disturbances and severe fatigue, which had a negative impact on their work well-being. Job-related stress contributed to sleep disturbances, and calls for further study on job-crafting and shift work coping. Support (If Any) Changhua Christian Hospital,Taichung, Taiwan