Central nervous system infection by Balamuthia mandrillaris is a rare and severe condition, which has a fatality rate of approximately 95% and often evades timely diagnosis due to its rarity and non-specific clinical manifestations. Here, we report a case of encephalomyelomeningitis caused by B. mandrillaris in a male who presented with transient coma, nausea, and vomiting when working in a garbage dump. Initial magnetic resonance imaging (MRI) of the brain showed normal signals. Despite receiving steroids as well as antibacterial and antiviral treatment, he developed urinary and fecal dysfunction, inability to walk, and deterioration of consciousness. Both brain and spinal cord MRI revealed abnormal findings, and next-generation sequencing of the cerebrospinal fluid showed the presence of B. mandrillaris. A combination of fluconazole and albendazole was administered; however, the patient deteriorated gradually and died 30 days after the onset. We suggest the unbiased metagenomic sequencing of the affected tissues/CSF in patients with CNS infections that are difficult to diagnose or treat, and multiple tests at different stages of the disease may be required.