In this article, we develop and meta-analytically test the relationship between job demands and resources and burnout, engagement, and safety outcomes in the workplace. In a meta-analysis of 203 independent samples (N = 186,440), we found support for a health impairment process and for a motivational process as mechanisms through which job demands and resources relate to safety outcomes. In particular, we found that job demands such as risks and hazards and complexity impair employees' health and positively relate to burnout. Likewise, we found support for job resources such as knowledge, autonomy, and a supportive environment motivating employees and positively relating to engagement. Job demands were found to hinder an employee with a negative relationship to engagement, whereas job resources were found to negatively relate to burnout. Finally, we found that burnout was negatively related to working safely but that engagement motivated employees and was positively related to working safely. Across industries, risks and hazards was the most consistent job demand and a supportive environment was the most consistent job resource in terms of explaining variance in burnout, engagement, and safety outcomes. The type of job demand that explained the most variance differed by industry, whereas a supportive environment remained consistent in explaining the most variance in all industries.