<p>Systemic lupus erythematosus (SLE) is an autoimmune disease that can involve the central nervous system (CNS), manifesting as a neuropsychiatric syndrome. Differentiating between neuropsychiatric systemic lupus erythematosus (NPSLE) and infections, such as West Nile encephalitis (WNE), as well as other etiologies, presents a significant diagnostic challenge and complicates the management of these patients. We present two cases of SLE patients with neuropsychiatric symptoms ultimately diagnosed as WNE and conducted a targeted literature review using bibliographic databases. We report two cases of SLE patients who presented with fever, cognitive decline, and rapid neurological deterioration. Both were considered to have NPSLE in the differential process, though later, they were found to have WNE after extensive and long diagnostic workups. Each case required subtle clinical management while awaiting confirmatory results. WNE can mimic CNS lupus, complicating the diagnosis and treatment. These cases emphasize the importance of considering infectious causes, especially in the face of the immunocompromised state of SLE patients, and balancing empirical treatments until definitive results are available. A literature review identified six additional cases of WNE in SLE patients. All cases involved diagnostic and management challenges similar to those in our cases, further underscoring the need to consider infectious etiologies in SLE patients presenting with neuropsychiatric symptoms.</p>