Tuberculosis is a rare but fatal trigger of secondary hemophagocytic lymphohistiocytosis (HLH). Its diagnosis is challenging because clinical manifestations overlap with HLH, and immunological tests may be falsely negative in HLH-related immune dysfunction. We report a case of a 34-year-old male with fever and pancytopenia. The patient’s diagnostic course was protracted and misleading: all conventional tuberculosis immunological tests were negative, and he initially did not meet HLH-2004 criteria. The diagnosis of TB-HLH was eventually established by a second bone marrow biopsy and metagenomic next-generation sequencing. We also reviewed 66 TB-HLH cases, revealing frequent negative immunological test results and showing that timely anti-tuberculosis therapy was associated with reduced mortality (78.3% vs. 15.0%, p < 0.001). This case and our review underscore the importance of early bone marrow biopsy and molecular testing in unexplained HLH, particularly when tuberculosis tests are negative. Given the high mortality and frequent diagnostic delay, clinicians should maintain a high index of suspicion and pursue aggressive diagnostic workup for tuberculosis in HLH patients without a clear trigger. Furthermore, we emphasize the need to raise awareness of TB-HLH and to interpret immunological test results with caution in HLH patients, as negative findings should not be used to exclude tuberculosis.