Purpose: To investigate nurse practitioners’ (NPs) experience of job strain in acute care settings, and to examine the factors that may affect job strain in that context. Design: Descriptive design using a national survey was employed. Methods: A total of 1396 NPs completed online surveys that recorded demographic characteristics and included a Job Content Questionnaire (JCQ), a Condition for Work Effectiveness Questionnaire (CWEQ), and the Dempster Practice Behavior Scale (DPBS). Multiple logistic regressions were conducted to explore the factors associated with job strain types. Findings: NPs were classified into job strain categories of passive (24.4%), active (31.4%), low (19.2%), or high (24.9%). The passive job strain type was associated with overtime hours, organizational empowerment, and autonomy. The active job type was associated with higher organizational empowerment and autonomy. The high-strain and low-strain job types were both associated with overtime hours and autonomy. Conclusion: Nearly 25% of acute care NPs are in a high job strain type. Organizational empowerment and autonomy were two major factors associated with the passive and active job strain types. Overtime hours and autonomy were both associated with the high-strain and low-strain job types. Clinical relevance: Supportive hospital/nursing leadership should acknowledge the impact of NP practice as they can contribute to the operational efficacy of their organization. Hospital administrators should provide a supportive practice environment by empowering NPs, enhancing autonomy, and addressing working conditions for NPs to decrease the odds of having a passive or high-strain job type in practice.