ObjectiveMajor depressive disorder (MDD), anxiety disorders, and somatic symptom disorder (SSD) are associated with quality of life (QoL) reduction. This cross-sectional study investigated the relationship between these conditions as categorical diagnoses and related psychopathologies with QoL, recognizing their frequent overlap. MethodsWe recruited a total of 403 clinical patients and healthy individuals, administering diagnostic interviews based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. QoL and psychopathologies were assessed using the WHO Quality of Life-BREF (WHOQOL-BREF) and several self-administered questionnaires, respectively. Multiple linear regression analyses examined the associations between psychiatric diagnoses, psychopathologies, and QoL. ResultsSSD and MDD were independently associated with impaired global (β = −0.318 and − 0.287) and all QoL domains (β = −0.307, −0.150, −0.125, and − 0.133, in physical, psychological, social, and environmental domains respectively for SSD; β = −0.278, −0.344, −0.275, and − 0.268 for MDD). The Beck Depression Inventory-II score showed pervasive associations with QoL (β = −0.390, −0.408, −0.685, −0.463, and − 0.420, in global, physical, psychological, social, and environmental domains). The Patient Health Questionnaire-15 and Health Anxiety Questionnaire scores were associated with global (β = −0.168 and − 0.181) and physical (β = −0.293 and − 0.121) QoL domain, while the Cognitions About Body and Health Questionnaire score was only associated with environmental QoL domain (β = −0.157). ConclusionSSD and MDD were independently associated with QoL impairment. Depressive symptoms were associated with all QoL domains, whereas somatic symptom burden and health anxiety primarily affected the physical QoL domain. Clinicians should consider concomitant psychopathologies when managing patients with depression, anxiety, or somatic symptoms.