Objective: To investigate self-stigma’s influence on schizophrenia patients’ quality of life and its mediated impact by various factors. Methods: This study adopted a cross-sectional design and randomly selected 170 hospitalized patients with schizophrenia for evaluation. The assessment tools included the Positive and Negative Syndrome Scale (PANSS), Self-Esteem Inventory (SEI), Connor-Davidson Resilience Scale (CD-RISC), Internalized Stigma of Mental Illness Scale (ISMI), Schizophrenia Quality of Life Scale (SQLS), Coping Questionnaire for Schizophrenia Patients (CQSP), and Social Support Rating Scale (SSRS). Correlation analysis, regression analysis, and mediation analysis were used to test the correlation and mediation effects. Results: Self-stigma had a significant impact on quality of life (T = 8.13, p = 0.00). Self-esteem (T = -2.11, p = 0.04) and coping strategies, specifically problem-solving (T = -2.58, p = 0.01) and avoidance (T = 4.65, p = 0.00), have a greater impact on self-stigma. When self-stigma is used as a mediator, the problem-solving factor in coping strategies has an indirect effect on quality of life, which is significant (AB = -0.16, P = 0.02), while the avoidance factor in coping strategies has a direct effect on quality of life, which is significant (C’ = 0.54, p < 0.001), and an indirect effect, which is also significant (AB = 0.25, p < 0.001). Conclusion: Self-stigma has a significant impact on quality of life. Clinical work to improve the quality of life of patients with schizophrenia should focus on self-stigma and factors that affect self-stigma, especially self-esteem and coping strategies.