Background: Systemic lupus erythematosus (SLE) is an autoimmune disease with diverse systemic manifestations, including neuropsychiatric involvement (NPSLE), which can vary in severity and prognosis. Diagnosing NPSLE remains challenging, necessitating reliable diagnostic markers. CXCL13, a B-cell chemokine implicated in SLE, has garnered attention for its potential role in NPSLE. Purpose: This study aimed to assess serum CXCL-13 levels in NPSLE patients compared to SLE patients without neuropsychiatric symptoms and healthy controls. Research Design: All study groups were studied CXCL-13 levels from blood samples. Study Sample: One hundred twenty-five participants were categorized into four groups: SLE patients with active NPSLE ( n = 6), SLE patients with inactive NPSLE ( n = 26), SLE patients without NPSLE ( n = 71), and healthy controls ( n = 22). Data Collection and Analyses: Serum samples were collected at the time of enrollment and CXCL-13 levels were analysed by Enzyme Linked ImmunoSorbent Assay (ELISA) method. Results: Results indicated significantly elevated CXCL-13 levels in active NPSLE patients compared to other SLE patient groups and healthy controls ( p < 0.001 for all). Patients with SLE, including those with inactive NPSLE or no history of NPSLE, had statistically significantly higher serum CXCL-13 levels compared to the control group ( p < 0.001). Additionally, serum CXCL-13 levels positively correlated with disease activity assessed by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Conclusion: This study underscores the association between serum CXCL-13 levels and neuropsychiatric involvement in SLE, as well as their correlation with disease activity. Moreover, previous research suggesting a link between CXCL-13 levels and clinical activity in SLE further supports its potential as a diagnostic marker for NPSLE. Nevertheless, further investigations are warranted to validate the utility of CXCL-13 as a diagnostic tool for NPSLE and its role in disease management.