The spectrum of infections in the central nervous system (CNS) has dramatically changed over centuries, attributing to high rate of microbial replication, mutations, and expansion across the new geographical regions. Vaccination reduced the burden of bacterial meningitis; however, serotype replacement, for example, S. pneumoniae remains a problem. Urgent blood and cerebrospinal fluid (CSF) sampling is recommended unless lumbar puncture is contraindicated. CSF Gram stain and culture, serology, and polymerase chain reaction (PCR) are the basic tests in isolating the organism. About 40 to 60% of CNS infections has undetermined diagnosis due to lack of standardised diagnostic tests and clinical case definitions that may lead to inappropriate use of antibiotics or untreated infection with long-term sequelae. Among case examples, Lyme cerebellitis presents with ataxia and nystagmus, with diagnostic delay and resultant delay in treatment. Early inclusion of specific advanced tests on CSF, molecular diagnostics serology, and next-generation sequencing (NGS) involves a comprehensive quantitative analysis of all pathogens. CfDNA has high sensitivity (75–91%) and specificity (81–100%) to detect any intracellular or extracellular pathogens. Early inclusion of CSF basic tests to beyond by including current evidence-based technology tools in conjunction with clinical presentation could improve quality in diagnosing early, any rare brain infections.