Abstract Background This case report presents a highly unusual and challenging medical case involving a 16-month-old previously healthy boy who developed encephalitis followed by Guillain-Barré Syndrome (GBS) as complications of multi-drug resistant Salmonella infection, despite an initial misdiagnosis of gastroenteritis and outpatient treatment with Cefixime. Methods The patient initially experienced an increase in stool frequency, accompanied by low-grade fevers, which was initially attributed to gastroenteritis. Outpatient treatment with oral Cefixime was started, but the child’s symptoms worsened, ultimately leading to high-grade fevers and an increase in vomiting and loose stools. In light of his clinical deterioration, he was admitted to our hospital with signs of mild metabolic acidosis and elevated inflammatory markers. During his hospitalization, the patient’s condition worsened, with drowsiness, irritability, and a generalized tonic-clonic seizure, prompting concern for brain involvement. Consequently, he underwent lumbar puncture, and neuroimaging, and received high-dose intravenous steroids. Further medical investigations including lumbar puncture and brain Magnetic Resonance Imaging (MRI), which revealed normal cerebrospinal fluid (CSF) analysis and non-enhancing white matter changes in the occipital region, respectively. In addition, a collected blood culture confirmed the presence of extensively multi-drug resistant Salmonella typhi and prompted an adjustment of antibiotics to intravenous Meropenem. Due to autonomic dysfunction, the patient was transferred to the Pediatric Intensive Care Unit (PICU) for close monitoring and specialized care. While in the PICU, he developed flaccid limb weakness and axial hypotonia. A repeat lumbar puncture was normal, but nerve conduction studies showed features of axonal polyneuropathy diagnosis, consistent with the diagnosis of GBS. To treat the encephalopathy and polyneuropathy, high-dose dexamethasone and Intravenous Immunoglobulin (IVIG) treatments were initiated, without necessitating respiratory or inotropic support. After receiving these treatments, the patient’s autonomic instability and motor strength improved, prompting his transfer back to the general pediatrics wards. He was treated with a 21-day course of IV Meropenem. Upon discharge, his motor power had returned to normal, and he displayed progress in movement transitions, including the ability to stand and walk independently, albeit with mild gait abnormalities. Results The co-occurrence of encephalitis and Guillain-Barré Syndrome due to Typhoid fever is exceedingly rare. The patient’s origin, with recent travel to Pakistan where extensively drug-resistant Salmonella typhi prevails, necessitates heightened awareness among healthcare providers. Initial misdiagnosis and inadequate antibiotics treatment may have contributed to encephalitis and polyneuropathy. High-dose dexamethasone and IVIG were pivotal in the patient’s treatment. While Typhoid fever-related neurological complications are infrequent, high-dose dexamethasone offers promise in reducing mortality and mitigating typhoid-induced encephalopathy. Importantly, IVIG is not conventionally employed in Salmonella encephalopalitis but was used due to polyneuropathy and its role in GBS management. Conclusion This exceptional pediatric case serves as a striking example of the possibility simultaneous encephalitis and Guillain-Barré Syndrome as rare complications of Typhoid fever. This case report underscores the importance of early diagnosis, prompt management with appropriate antibiotics and caution of possible neurological complications. Furthermore, it calls for further research into the role of high-dose glucocorticoids and IVIG in the management of extensively multi-drug resistant Salmonella infection and its neurological complications.