The multidrug-resistant (MDR) bacterium Chryseobacterium indologenes causes rare and challenging infections of the central nervous system, without standardized treatment guidelines. Trimethoprim-sulfamethoxazole (TMP-SMX) is the most common first-line treatment, but its effectiveness is not always reliable. The article describes the case of a 25-year-old postpartum woman who developed MDR C. indologenes meningitis and brain abscess after neurosurgery. The infection did not respond to meropenem or TMP-SMX. Based on antibiotic susceptibility testing, rifampin monotherapy was instituted, leading to rapid clinical and microbiological recovery. The patient received 24 days of rifampin treatment and there was no recurrence during the 20-month follow-up. This is the first report of successful monotherapy with rifampin in CNS infection of MDR C. indologenes unresponsive to TMP-SMX. Susceptibility testing and rifampin are emerging as a key salvage option when first-line treatment fails.