A 25-year-old man had a month-long cough, expectoration of mucus, and fever up to 41°C. He was diagnosed with a brain abscess at a local hospital and treated with ceftriaxone, acyclovir, and mannitol, later with vancomycin and meropenem, but his condition worsened with disturbances of consciousness, dysarthria, and new abscesses. After admission to a specialized institution, metagenomic sequencing (mNGS) of cerebrospinal fluid revealed the bacteria Prevotella loescheii and Porphyromonas gingivalis from the oral flora. The patient underwent endoscopic lavage of the abscess with drainage while maintaining the antibiotic regimen, which resulted in resolution of the abscesses and improvement of consciousness. The infection was from an oropharyngeal source. The case highlights the value of mNGS in the detection of anaerobic pathogens in culture-negative refractory brain abscesses. A combination of targeted antibiotic therapy and endoscopic intervention has been successful in multiple abscesses.