TNF, a proinflammatory cytokine, plays a dual role in human tuberculosis (TB). It is essential for protective immunity against Mycobacterium tuberculosis (Mtb) but also contributes to immunopathology. TNF is primarily produced by phagocytes in the lungs during early Mtb infection and is involved in granuloma formation, macrophage recruitment, and chronic infection prevention. In animal models, TNF, along with chemokines, helps control mycobacterial growth in granulomas. However, anti-TNF therapy, while effective for immune diseases like rheumatoid arthritis, can reactivate TB. TNF-associated inflammation also contributes to cachexia in TB patients. This review highlights TNF's multifaceted role in TB pathogenesis and prevention, emphasizing the need to study TNF and its receptors to develop therapies targeting TNF signaling. TNF is crucial for M1 macrophage responses, immunometabolic remodeling, trained immunity, and apoptosis, which are vital for protective immunity. However, excessive TNF production and mitochondrial damage can lead to necrotic cell death and TB progression. Understanding TNF's regulatory mechanisms is essential for developing effective TB interventions. TNF also influences granuloma formation, immune activation, and the balance between protective and harmful immune responses. The interplay between TNF and other immune pathways, such as autophagy and apoptosis, is critical for controlling TB. Further research is needed to explore TNF's role in TB and develop targeted therapies.TNF, a proinflammatory cytokine, plays a dual role in human tuberculosis (TB). It is essential for protective immunity against Mycobacterium tuberculosis (Mtb) but also contributes to immunopathology. TNF is primarily produced by phagocytes in the lungs during early Mtb infection and is involved in granuloma formation, macrophage recruitment, and chronic infection prevention. In animal models, TNF, along with chemokines, helps control mycobacterial growth in granulomas. However, anti-TNF therapy, while effective for immune diseases like rheumatoid arthritis, can reactivate TB. TNF-associated inflammation also contributes to cachexia in TB patients. This review highlights TNF's multifaceted role in TB pathogenesis and prevention, emphasizing the need to study TNF and its receptors to develop therapies targeting TNF signaling. TNF is crucial for M1 macrophage responses, immunometabolic remodeling, trained immunity, and apoptosis, which are vital for protective immunity. However, excessive TNF production and mitochondrial damage can lead to necrotic cell death and TB progression. Understanding TNF's regulatory mechanisms is essential for developing effective TB interventions. TNF also influences granuloma formation, immune activation, and the balance between protective and harmful immune responses. The interplay between TNF and other immune pathways, such as autophagy and apoptosis, is critical for controlling TB. Further research is needed to explore TNF's role in TB and develop targeted therapies.