The incidence of nontuberculous mycobacterial (NTM) infection has been increasing globally. Further, it has been reported that early NTM infection diagnosis and treatment can considerably improve patient prognosis. However, traditional methods for detecting pathogenic microorganisms are associated with several limitations, and optimal treatment regimens for several NTM infections have not yet been established. Here, we report the case of a 22-year-old woman with renal and lymph node Mycobacterium xenopi infection. This patient presented with repeated fever and systemic lymphadenopathy events for more than 2 years, but the etiology of the disease was unclear. We performed metagenomic next-generation sequencing (mNGS) using tissue sections from the patient's left kidney and successfully identified M. xenopi. Thereafter, the patient's condition was effectively controlled via treatment with rifampicin, clarithromycin, and ethambutol hydrochloride (orally administered after hemodialysis). Further, this case showed that the clinical symptoms of NTM infection are atypical and highly occult, especially for extrapulmonary NTM infections, which are difficult to diagnose. Therefore, mNGS may be a powerful tool for diagnosing NTM infections. The combination therapy used showed efficacy and thus could serve as a reference treatment for kidney and lymph node M. xenopi infection.