This cross-sectional study examined the relationship between work-related stress, cortisol, and C-reactive protein (CRP) in predicting metabolic syndrome (MtS). Self-reported work stress measured by the effort reward imbalance ratio (ERI), anthropometric data, CRP, and saliva cortisol were collected from 204 healthy Jordanian male workers. ERI and cortisol were significantly associated with the presence of MtS (OR = 4.74, 95% CI: 2.13–10.55; OR = 3.03, 95% CI: 2.08–4.40; OR = 11.50, 95% CI: 2.16–59.14, respectively). The odds of MtS in men with high ERI and high cortisol were significantly higher than that of men with low ERI and low cortisol (OR = 11.50, 95% CI: 2.16–59.14). CRP was significantly associated with MtS (OR = 2.51, 95% CI: 1.50–4.20). The odds of MtS were significantly higher in centrally obese men with both high ERI and CRP level. Thus, high ERI along with high cortisol or high CRP increases the risk for MtS, especially among centrally obese men.