Objectives The aim of study was to evaluate the quality of life (QOL) across different diagnostic categories in inpatients with severe mental illness (SMI) and examine its associations with sociodemographic, illness-related characteristics, and perceived social support. Methods A cross-sectional study was conducted. A total of 280 patients, consecutively admitted, were recruited in the Adult Psychiatric Department of the University Hospital Larissa, Larisa, Greece. QOL and social support were measured using the World Health Organization Quality of Life - BREF (WHOQOL-BREF) and the Social Support Questionnaire - Short Form (SSQ-6) scales, along with sociodemographic and clinical data. Results The social relationships domain of the WHOQOL-BREF received the lowest score across all diagnoses. Significant differences in QOL were noted based on the type of admission, though not by diagnosis. Women reported significantly worse physical (-0.90, p=0.019), mental (-1.02, p=0.020), and overall QOL (-1.09, p=0.035) compared to men. Age was significantly associated with environmental (-0.03, p=0.016) and overall QOL (-0.05, p=0.014). Homelessness was linked to poorer QOL in social (-2.42, p=0.040) and environmental domains (-2.16, p=0.020). Urbanicity (1.09, p=0.041) and retirement (-1.48, p=0.031) were also significant factors for global QOL. Social support satisfaction had a significant positive association with the social relationship dimension (0.06, p=0.022), while the support network had a marginal effect (0.05, p=0.080). Outpatient monitoring was significantly associated with the mental health dimension (-0.94, p=0.032). Multiple regression analyses indicated that gender, marital status, age, work status, number of cohabitants, type of residence, and social support were significantly associated with global and specific QOL dimensions. Conclusions This study explores the QOL in inpatients with SMI, admitted both involuntarily and voluntarily, emphasizing the impact of sociodemographic, clinical factors, and perceived social support. Key predictors of QOL include female gender, homelessness, retirement, and perceived social support. Routine QOL assessments combined with gender- specific and social support interventions are essential for improving patient outcome.