A 44-year-old woman undergoing therapy for acute promyelocytic leukemia (APL) developed disseminated tuberculosis. Mycobacterium tuberculosis (TB) was isolated from the blood and sputum. Initial drug susceptibility testing (DST) of the blood isolate revealed resistance to isoniazid and ethambutol but the sputum isolate showed no resistance. Due to drug resistance concerns, the patient was treated with multiple second and third-line drugs, and suffered from drug side effects. To further investigate the DST discrepancies, whole genome sequencing (WGS) was performed on both isolates. No known resistance mutations to first line or second line drugs were identified in either isolate, which was confirmed by additional susceptibility testing performed by a different reference laboratory and the California Department of Public Health (CDPH) laboratory. Treatment was reduced to a simpler and less toxic regimen due to these investigations. WGS is shown to be a valuable tool for resolving discordant phenotypic DST results of TB isolates and has the potential to provide accurate and timely results guiding appropriate therapy in the clinical setting.