<b><i>Background:</i></b> The clinical spectrum of systemic nocardiosis encompasses pulmonary and disseminated disease. Central nervous system (CNS) involvement is an important feature of disseminated disease with significant mortality and high relapse rate, especially in those with suppressed cell-mediated immunity. This systematic review aimed to evaluate the epidemiology, clinical features, diagnosis, therapeutic interventions, and outcome in patients with CNS nocardiosis. <b><i>Methods:</i></b> A literature search was performed in major databases (PubMed, Google Scholar, and Scopus) by using distinct keywords: “CNS disease,” “<i>Nocardia</i>,” “meningitis,” “brain abscess,” “disseminated disease,” and “Cotrimoxazole.” We included all patients ≥18 years with CNS nocardiosis reported between January 2000 and December 2020. <b><i>Results:</i></b> A total of 129 papers were included in the final analysis. The mean age of patients was 55 ± 16 years, and the majority were male (70.8%). <i>Nocardia farcinica</i> was the commonest species (39.6%), followed by <i>Nocardia nova</i> (5.9%). Thirty-four percent of the patients were found to be immunocompetent. Corticosteroid use was the most common predisposing factor (55.8%). Among neuroimaging findings, brain abscess was most common (86.9%), followed by leptomeningeal enhancement (12.1%). The overall case-fatality rate in CNS disease was 22.8%. On multivariate analysis, patients who underwent surgery (OR 2.4, 95% CI 0.99–4.11, <i>p</i> value 0.046) had better survival than those treated with antimicrobial therapy alone. Immunodeficient state (OR 0.32, 95% CI 0.15–0.90, <i>p</i> value 0.019) was independently associated with poor outcome. <b><i>Conclusion:</i></b> CNS nocardiosis carries significant mortality, especially in immunodeficient patients. We advocate the use of surgery combined with antimicrobials to improve clinical outcome.