The present study aimed to examine the relationship between toxic leadership and the job-related affective well-being of workers with the mediating role of job stress. Research population consisted of knowledge workers in knowledge-based organizations, 213 of whom were selected and filled in the Job-Related Affective Well-being Scale (JAWS) [1], Measures of Job Stressors and Strains (MJSS) [2], and Toxic Leadership Scale (TLS) [3]. Data were analyzed through correlation and path analyses. Results showed the significant direct and indirect effects of toxic leadership, quantitative workload, organizational constraints, and interpersonal conflicts on job-related affective well-being. Four variables (interpersonal conflicts, organizational constraints, quantitative workload, and toxic leadership) accounted for 13% of the variance of job-related affective well-being. Moreover, results of the fit of the model revealed a direct significant effect of toxic leadership on interpersonal conflicts where it accounted for 12% of the variance of interpersonal conflicts. Also, accounting for 9% of the variance of quantitative workload, toxic leadership was demonstrated to have a direct significant effect on quantitative workload. Results also indicated a direct significant effect of toxic leadership on organizational constraints where it accounted for 11% of the variance of organizational constraints. Finally, the necessity of paying attention to organizational management styles was discussed.