This article explores the roles of arginine and tryptophan metabolism in macrophage activation during tuberculosis (TB). It highlights the functional heterogeneity of human M1 and M2 macrophages, which are critical in the immune response to *Mycobacterium tuberculosis* (MTB). M1 macrophages, activated by IFN-γ, produce nitric oxide (NO) through inducible nitric oxide synthase (iNOS), which helps control MTB. In contrast, M2 macrophages, driven by IL-4, express Arginase-1 (Arg1), converting arginine to ornithine, which promotes tissue repair but can also suppress immune responses. The balance between citrulline and ornithine production, determined by arginine metabolism, is crucial for controlling MTB infection. Tryptophan catabolism, upregulated by IDO1, is also significant, with its products influencing immune responses and TB progression. Sirtuin proteins, particularly Sirt2 and Sirt5, are highlighted as key regulators of arginine and tryptophan metabolism. Sirt2 is more active in M2 macrophages and influences IL4i1 expression, affecting macrophage polarization. Sirt5 is more prominent in M1 macrophages and regulates the urea cycle, enhancing citrulline production. These proteins play a role in NAD⁺ metabolism, which is vital for immune cell function and energy production. The article also discusses the dual role of arginine in MTB infection, where it is essential for macrophage development and pathogen elimination. MTB can acquire arginine directly or synthesize it from glutamine, highlighting the importance of arginine availability in host-pathogen interactions. Tryptophan catabolism, particularly through IDO1, leads to the production of kynurenine, which can modulate immune responses and influence macrophage polarization. The interplay between tryptophan catabolism and NAD⁺ metabolism is crucial for maintaining immune homeostasis and combating TB. The study suggests that targeting these metabolic pathways, particularly through Sirtuin proteins, could offer new therapeutic strategies for TB. Inhibitors of IDO1 and other enzymes in tryptophan catabolism have shown promise in reducing MTB burden and improving immune responses. The complex interactions between arginine, tryptophan, and Sirtuin proteins underscore the need for further research to develop effective host-directed therapies for TB.This article explores the roles of arginine and tryptophan metabolism in macrophage activation during tuberculosis (TB). It highlights the functional heterogeneity of human M1 and M2 macrophages, which are critical in the immune response to *Mycobacterium tuberculosis* (MTB). M1 macrophages, activated by IFN-γ, produce nitric oxide (NO) through inducible nitric oxide synthase (iNOS), which helps control MTB. In contrast, M2 macrophages, driven by IL-4, express Arginase-1 (Arg1), converting arginine to ornithine, which promotes tissue repair but can also suppress immune responses. The balance between citrulline and ornithine production, determined by arginine metabolism, is crucial for controlling MTB infection. Tryptophan catabolism, upregulated by IDO1, is also significant, with its products influencing immune responses and TB progression. Sirtuin proteins, particularly Sirt2 and Sirt5, are highlighted as key regulators of arginine and tryptophan metabolism. Sirt2 is more active in M2 macrophages and influences IL4i1 expression, affecting macrophage polarization. Sirt5 is more prominent in M1 macrophages and regulates the urea cycle, enhancing citrulline production. These proteins play a role in NAD⁺ metabolism, which is vital for immune cell function and energy production. The article also discusses the dual role of arginine in MTB infection, where it is essential for macrophage development and pathogen elimination. MTB can acquire arginine directly or synthesize it from glutamine, highlighting the importance of arginine availability in host-pathogen interactions. Tryptophan catabolism, particularly through IDO1, leads to the production of kynurenine, which can modulate immune responses and influence macrophage polarization. The interplay between tryptophan catabolism and NAD⁺ metabolism is crucial for maintaining immune homeostasis and combating TB. The study suggests that targeting these metabolic pathways, particularly through Sirtuin proteins, could offer new therapeutic strategies for TB. Inhibitors of IDO1 and other enzymes in tryptophan catabolism have shown promise in reducing MTB burden and improving immune responses. The complex interactions between arginine, tryptophan, and Sirtuin proteins underscore the need for further research to develop effective host-directed therapies for TB.