Background <p>Behçet’s disease (BD) is a chronic, inflammatory multisystem disease that has impact both physical health and mental well-being. However, the psychological impact of BD remains underexplored, particularly in Arabic-speaking populations. The aim of this study was to assess the prevalence of anxiety and depression in Arabic-speaking BD patients, evaluate their association with health-related quality of life (HRQoL), and identify key predictors of psychological distress in these patients.</p> Methods <p>This cross-sectional study included 192 BD patients recruited from our rheumatology clinic and an online survey among BD patients. Psychological distress was assessed using the Arabic version of Hospital Anxiety and Depression Scale (HADS), while HRQoL was assessed via the Arabic version of Short Form 36 (SF-36) Health Survey. Univariate and multivariate regression analyses were performed to identify main factors linked with anxiety and depression.</p> Results <p>Anxiety and depression were highly prevalent in BD patients, with 53.1% of the study participants exhibiting abnormal anxiety levels and 38.5% showing abnormal depression scores. Higher levels of psychological distress were statistically significantly associated with BD disease activity and elevated erythrocyte sedimentation rate levels (<i>p</i> = 0.017). Additionally, patients with greater anxiety and depression scores had significantly lower HRQoL scores across all SF-36 domains (<i>p</i> &lt; 0.001). Gender differences were observed, with females showing higher anxiety rates (<i>p</i> = 0.006).</p> Conclusions <p>Anxiety and depression are major contributors to reduced HRQoL in BD patients, necessitating a multidisciplinary approach that integrates mental health care into disease management.</p> Clinical trial number <p>Not applicable.</p>