PurposeTuberculosis sepsis (TBS) is sepsis due to theMycobacteriumspecies causing tuberculosis (TB). It seems to be rare in HIV-negative patients and mainly individual case reports have been reported. This systematic review summarizes the epidemiology, clinical features, and treatment outcomes of TBS in HIV-negative patients.MethodsAn electronic search of PubMed, Embase, Web of Science, and Google Scholar was performed to identify published case reports of TBS between January 1991 and September 2022.ResultsTwenty-five articles reported 28 cases of TBS in HIV-negative patients, among which 54% (15/28) were women; with 50% (14/28) of patients not having reported predisposing factors. A total of 64% (18/28) of patients died, and the diagnosis was obtained for many of them only post-mortem. Two of the reports mentioned the BCG vaccination status. A higher proportion of deaths occurred in patients with delayed diagnosis of sepsis. The probability of survival of patients diagnosed with tuberculosis sepsis was 68% on day 10; 41% on day 20; and 33% on day 30 after admission.ConclusionsOur review showed TBS occurred in HIV-negative patients and some of them have no known immunocompromised underlying co-morbidity. TBS might not be rare as clinicians thought but might be prone to be missed. In endemic settings,M. tuberculosisetiology of sepsis should be accounted for early, irrespective of HIV infection status.Supplementary InformationThe online version contains supplementary material available at 10.1007/s15010-022-01950-4.