Mycobacterium abscessus (Mab) ranks among the most drug-resistant and therapeutically recalcitrant rapidly growing non-tuberculous mycobacteria and has emerged as a persistent clinical challenge in pulmonary and skin/soft-tissue infections. Macrophages, as central effectors of innate immunity, paradoxically constitute the principal intracellular niche that Mab exploits for survival and immune evasion. The pathogen exists in two distinct colony morphotypes—smooth (Mab-S) and rough (Mab-R)—that differ in host recognition, intracellular trafficking, and the immune responses they elicit. Mab-S is shielded by a surface glycopeptidolipid (GPL) layer that masks TLR2 ligands, forms loner phagosomes that resist phagosome–lysosome fusion, and blocks autophagic flux through the ESX-3/ESX-4 secretion systems. By contrast, GPL-deficient Mab-R exposes TLR2 ligands, generates social phagosomes that fuse rapidly with lysosomes, and activates NLRP3/GSDMD-mediated pyroptosis, thereby enabling bacterial dissemination. Mab further subverts host cell death pathways—apoptosis, necroptosis, and ferroptosis—and manipulates M1/M2 macrophage polarization to sustain an intracellular niche permissive for persistence. In this review, we systematically dissect the molecular mechanisms governing macrophage–Mab interactions and evaluate therapeutic strategies targeting this interface. We propose a tripartite treatment framework integrating immunomodulation, antibiotics, and virulence factor inhibition. Finally, we identify the dynamics of macrophage polarization within distinct infection microenvironments as a central priority for future mechanistic and translational investigation. This review advances understanding of Mab immune evasion and provides a conceptual roadmap for developing effective multimodal interventions.