Introduction. Standard culture methods may fail to detect the causative agents of bacterial infection for various reasons including specimen collection after antibiotic administration, or when standard techniques or environmental conditions are not appropriate for growth of the microorganisms. Conventional 16S rRNA gene sequencing is sometimes a useful alternative technique for identification of bacteria, but is confounded by polymicrobial infection. We present a case of a patient who developed a serious neurological infection for which causative oral flora organisms were observed by microscopy, failed to culture but were identified by next-generation DNA sequencing. Case presentation. A male in his forties developed sinus pain and congestion, followed by facial and eye pain, and several weeks later acute-onset confusion and neck stiffness. Cerebrospinal fluid examination revealed pleocytosis and several bacterial morphologies, which were subsequently identified by next-generation sequencing as oral flora constituents Porphyromonas endodontalis , Fusobacterium nucleatum , Streptococcus constellatus , Prevotella species and Parvimonas micra . Conclusion. Oral flora can cause meningoencephalitis and brain abscess formation if translocation occurs by injury or surgical procedures. Next-generation sequencing is often not available at healthcare facilities, or when available may not have been validated for a wide spectrum of specimen sources, but is available at reference laboratories and should be considered when routine methods fail to provide a diagnosis for serious infections.