Background <p>Patients with chronic hepatitis B (CHB) are at risk of developing psychiatric symptoms such as depression, anxiety, and fatigue, which may adversely affect quality of life, treatment adherence, and disease outcomes. Emerging evidence suggests that these psychological symptoms are influenced not only by psychosocial stressors but also by biological mechanisms related to hepatic necroinflammation and fibrosis. This study aimed to investigate the relationship between depression, anxiety, fatigue, and non-invasive liver fibrosis scores in patients with CHB.</p> Methods <p>In this cross-sectional study, 200 adult CHB patients were consecutively recruited from a university-affiliated hospital outpatient clinic between September 2023 and February 2024. Patients with acute HBV, cirrhosis, hepatocellular carcinoma, psychiatric comorbidities, or major systemic illnesses were excluded. Psychiatric symptoms were assessed using the validated versions of the Hospital Anxiety and Depression Scale (HADS) and the Fatigue Severity Scale (FSS). Liver fibrosis and necroinflammatory activity were evaluated using non-invasive markers, including AST/ALT ratio (AAR), APRI, FIB-4, and Age-Platelet Index (API). Multivariable logistic regression was used to identify independent predictors of depression, anxiety, and fatigue.</p> Results <p>Of the 200 patients, 21.0% had depression, 6.5% had anxiety, and 27.0% reported significant fatigue. APRI values were significantly higher in patients with fatigue (<i>p</i> = 0.002), and API scores were significantly higher in those with anxiety (<i>p</i> = 0.035). No significant association was found between non-invasive fibrosis indices and depression, although patients with higher depression scores tended to have elevated AAR values. Anxiety was more frequent among unmarried individuals (<i>p</i> &lt; 0.001), and fatigue was more common in patients receiving antiviral treatment (<i>p</i> = 0.027).</p> Conclusions <p>Psychiatric symptoms are prevalent among CHB patients and show significant associations with both psychosocial and biological disease factors. Fatigue was associated with hepatic injury reflected by APRI, and anxiety with early fibrosis markers such as API. These findings underscore the need to integrate routine <i>psychiatric</i> screening for depression, anxiety, and fatigue into CHB management, and to address these symptoms through comprehensive, multidisciplinary care approaches to improve patient well-being and treatment adherence.</p> Trial registration <p>Not applicable. This study is a cross-sectional observational design and did not require prospective registration.</p>