Background: Schizophrenia is a chronic and severe mental illness that ultimately leads to reduced quality of life (QoL). Over the years, QoL has emerged as an important outcome in the treatment of schizophrenia patients, but the role of psychosocial variables in determining QoL is still ambiguous. Therefore, in the present research, demographic, clinical and psychosocial variables were examined for their influence on QoL. Methods: We conducted a prospective and cross-sectional study on a sample of 139 patients with schizophrenia (72.7% females, age 48.17 ± 10.22) attending an outpatient service. QoL was measured using Schizophrenia Quality of Life Revision-4 (SQLR4) and internalised stigma, self-esteem, perceived social support, resilience and coping mechanisms were assessed using a battery of standardized self-report scales. Results: Female patients and those less adherent to treatment had reduced cognition and vitality QoL. The worst QoL in all domains was observed in patients with a younger age at illness onset and with six or more hospitalizations. Regression analysis indicated that reduced self-esteem, perceived social support, a larger number of hospitalization and increased internalised stigma predicted poorer overall QoL and accounted for 44.9% in the variance in SQLSR4 global score (adjusted R2 = 0.449, p = 0.046). Conclusions: Routine assessment of internalised stigma, self-esteem and perceived social support, in addition to demographic and clinical variables and addressing possible deficits in these areas through personalized intervention, could improve QoL in schizophrenia patients.