Introduction: Clinical psychological features may impact a person's aptitude to deal with chronic diseases, leading to emotional distress, suffering, and a worse perceived quality of life (QoL). Chronic diseases are largely represented, and their incidence is constantly increasing all over the world. Type 2 Diabetes Mellitus (T2DM) is one of the most common chronic diseases and it is very difficult to manage, demanding long term self-management, which improves the perceived QoL. The aim of this study was to explore defense mechanisms, depression, QoL, time since diagnosis, and metabolic control in T2DM patients. Methods: 51 patients with T2DM were assessed through a psychodiagnostic battery: Beck Depression Inventory-II, the 36-Item Short Form Health Survey, including indexes of Physical and Mental Component Summary and the Defense Mechanisms Inventory. Times since DM diagnosis and glycated hemoglobin values were detected. Results: Participants were mainly female (62.74%), with a mean age of 66.1 years. T2DM time since diagnosis was 11.77 years (SD = 7.1). Mild depression was detected (with an overall score between 13 and 19). Projection was significantly associated with higher depression and with lower physical well-being; Principalization was negatively associated with depression and positively with both physical and mental well-being. Turning Against Self correlated positively with physical well-being and negatively with mental well-being. Reversal was associated with lower depression and higher mental well-being. A negative high correlation emerged between depression and mental wellbeing. Finally, a significant relationship was found between Projection and higher time since diagnosis (r = 0.31, p < 0.05).