Background: Psoriasis is associated with a high psychological burden and comorbidities, such as depression and anxiety. The aim of this study was to evaluate the psychopathological profile of patients with moderate-to-severe plaque psoriasis under systemic treatment and to explore the association between DLQI and alexithymia, depression, and other psychopathological disorders. Methods: In this monocentric, prospective clinical study, 104 adult patients with moderate-to-severe plaque psoriasis were evaluated according to the disease severity (measured by PASI) influence of psoriasis on their quality of life (measured by DLQI) and their psychopathological profile (measured by the BDI, TAS-20, and SCL-90 questionnaires). Results: The psoriasis patients exhibited high levels of psychopathological symptoms, particularly for depression, obsessive-compulsive behavior, somatization, interpersonal sensitivity, and anxiety. More than half of the psoriatic patients (56.7%) were diagnosed with minimal depression, 26.9% with mild depression, and 16.3% with moderate or severe depression. The symptoms of possible and confirmed alexithymia were present in 19.2% and 15.4% of the patients, respectively. The patients with alexithymia appeared to experience a more significant impact on their QoL. Specifically, the percentage of patients with alexithymia/possible alexithymia who had a DLQI of ≥2 was 77.8% vs. 51.5% in those without alexithymia. Conclusions: Our study illuminates the intricate connection between the disease severity and psychological components that impact the QoL of patients with moderate-to-severe plaque psoriasis. It is advised that clinicians adopt a comprehensive approach to managing psoriasis, which involves addressing both the physical symptoms of the condition and the psychological impact. In cases of patients with a DLQI of ≥2, despite adequate clinical responses, evaluating the possible coexistence of general psychopathology is recommended.