Purpose: To investigate the combined role of irrational beliefs, anxiety and depression in the 10-year incidence of type 2 diabetes, and the underlying effect of biochemical, and socio-behavioural factors. Methods: Within the context of the ATTICA cohort study (2002–2012), 853 participants without evidence of CVD [453 men (45 ± 13 years) and 400 women (44 ± 18 years)] underwent psychological evaluation through the Irrational Beliefs Inventory (IBI) (range 0–88), the Zung Self-Rating-Depression-Scale (ZDRS) and the State-Trait-Anxiety-Inventory (STAI). Diagnosis of diabetes at follow-up examination was based on the criteria of the American Diabetes Association (ADA). Results: Mean IBI score was 53 ± 10 in men and 51 ± 11 in women (p = 0.68). Participants with high irrational beliefs who also had anxiety symptoms had a 93% excess risk of developing diabetes during the 10-year follow-up (Hazard Ratio 1.93; 95%CI 1.34, 2.78) as compared to those without anxiety. Moreover, diabetes risk was 73% higher among individuals with high levels of irrational beliefs and depression as compared to those where depression was absent (1.73; 1.21, 2.46). Lower education status, family history of diabetes, hypercholesterolemia, high BMI, as well as tumor necrosis factor and total antioxidant capacity were revealed as mediating risk factors related to the tested associations. Conclusion: Irrational beliefs among apparently healthy adults trigger depression and anxiety symptomatology, and through the increased inflammation and oxidative stress profile, were associated with increased diabetes risk. This observation moves psychological research a step forward in supporting and guiding primary prevention of mental health and metabolic conditions.