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Background: Although mood disorders are prevalent among systemic lupus erythematosus (SLE) patients, they are usually underrecognized. This study aimed to estimate the prevalence of anxiety and depression among Saudi SLE patients. Methods: This cross-sectional study was conducted among SLE patients from July 2022 to June 2023 in the Eastern Province of Saudi Arabia. A self-reported questionnaire was used to collect the data through validated tools including the Hamilton Anxiety Rating Scale-A and the Beck Depression Inventory score. Results: There were 133 females (91.7%) and 12 males (8.3%) included in this study. Based on the HAM-A score, 45.5% of participants had an anxiety disorder, and according to the BDI score, 46.2% had a depression disorder. Anxiety and depression were significantly associated with a longer duration of SLE, unemployment status, smoking, and the presence of comorbidities. Moreover, the present study found a significant association between depression and male gender. Conclusion: This study found that Saudi SLE patients have a high prevalence of both anxiety and depression. Therefore, SLE patients should be screened for neuropsychiatric disorders during routine follow-ups and managed as early as possible.