Background <p>Guillain–Barré syndrome (GBS) is an acute, immune-mediated polyneuropathy classically characterized by rapidly progressive, symmetrical limb weakness and areflexia. Although neuropsychiatric manifestations have been described, they remain uncommon and may lead to diagnostic delay or misattribution to primary psychiatric illness.</p> Case presentation <p>We describe a 58-year-old woman with a history of rheumatoid arthritis who presented with hematemesis secondary to gastritis and altered mental status (AMS), preceded by several weeks of progressive behavioral changes, including withdrawal, dysphoria, hallucinations, and disorientation. During hospitalization, her mental status continued to decline despite trials of antipsychotic and benzodiazepine therapy. Neurological examination revealed progressive ascending weakness, areflexia, and sensory deficits. Cerebrospinal fluid analysis demonstrated albuminocytologic dissociation. In the absence of electrophysiological confirmation, the findings raised concern for an immune-mediated polyradiculoneuropathy such as Guillain–Barré syndrome; however, definitive classification was not possible because electrophysiological testing was not performed. The patient was treated with a five-day course of intravenous immunoglobulin (IVIG), after which both motor function and mental status improved; however, treatment response was interpreted cautiously because IVIG is not disease-specific.</p> Conclusion <p>This case highlights the diagnostic complexity of neuropsychiatric presentations in suspected GBS. The prominence and early onset of psychiatric symptoms necessitated a broad differential diagnosis, including delirium, metabolic encephalopathy, autoimmune encephalitis, and acute porphyria. Additionally, the patient’s history of rheumatoid arthritis raised consideration of alternative immune-mediated neuropathies, including vasculitic neuropathy. Importantly, autoimmune encephalitis could not be excluded due to the absence of neuroimaging, EEG, and antibody testing. Furthermore, clinical improvement following IVIG is not disease-specific and may occur in multiple autoimmune conditions. This case underscores the diagnostic tension between peripheral and central nervous system autoimmune processes in the setting of incomplete diagnostic data. GBS should remain a consideration in patients presenting with concurrent neurological and psychiatric symptoms; however, caution is warranted when diagnostic studies are limited. This case emphasizes the importance of maintaining a broad differential diagnosis and highlights the potential for overlap between peripheral neuropathies and central autoimmune encephalopathies. Early multidisciplinary evaluation and careful interpretation of treatment response are essential for optimizing patient outcomes. This report should be interpreted as an educational case illustrating the diagnostic complexity of overlapping neuropsychiatric and peripheral neurological manifestations rather than as definitive evidence of an atypical presentation of Guillain–Barré syndrome.</p>