Background: Nurses often experience a wide variety of stressful situations. Excessive work stress influences the physical and mental health of nurses and decreases their life quality and professional efficacy. In addition, high levels of psychological stress may cause job dissatisfaction and job strain. Purpose: The objective of this studywas to explore the relationship between several work-related risk factors and job satisfaction in Iranian nurses. Methods: A cross-sectional study was conducted on 730 nurses from four public hospitals in, respectively, northern, southern, eastern, and western Iran. Variables in the job demand–control– support (JDCS) model were measured using the Job Content Questionnaire, and job satisfaction was measured using the Minnesota Satisfaction Questionnaire. Results: Themean score for job satisfactionwas 62.94 ± 14.24, which is considered moderate. Nurses with a low level of job satisfaction had significantly higher psychological and physical job demands (p < .05). Significant relationships were found between job satisfaction and several dimensions of the JDCS model, including psychological job demands (β = −0.11, p < .001), physical job demands (β = −0.86, p = .004), skill discretion (β = 0.48, p = .033), decision authority (β = 0.43, p = .028), and supervisor support (β = 1.85, p = .004). The sociodemographic and JDCS model variables used in this study explained 42% of the variation in job satisfaction (R2 = .42). Conclusions/Implications for Practice: Enhancing the job satisfaction of nurses is possible by creating a balance between job demands, job control, and social support.