Natural Killer (NK) cells, as pivotal effectors of the innate immune system, bridge innate and adaptive immunity through their cytolytic potential, cytokine secretion, and immunoregulatory interactions, yet exhibit a bifurcated functionality in autoimmune disorders, exerting both protective and pathogenic roles that are finely tuned by subset identity, receptor–ligand balance, and the inflammatory microenvironment. This comprehensive chapter synthesizes contemporary insights into NK cell immunobiology across a broad spectrum of organ-specific and systemic autoimmune diseases, with particular focus on disorders of the nervous system (multiple sclerosis, neuromyelitis optica spectrum disorder, myasthenia gravis), rheumatologic conditions (rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s syndrome), and inflammatory skin diseases (psoriasis, alopecia areata, pemphigus vulgaris, Behçet’s disease). Recurring mechanisms highlight this bifurcated nature: CD56bright NK cells frequently confer protection by suppressing autoreactive T and B lymphocytes through granzyme K-dependent apoptosis, TRAIL signaling, and DNAM-1-mediated cytotoxicity, whereas CD56dim and tissue-resident subsets can drive pathogenesis via antibody-dependent cellular cytotoxicity (ADCC), RANKL/M-CSF-induced osteoclastogenesis, NKp30-B7H6 interactions, and proinflammatory cytokine secretion. Dysregulated activating and inhibitory receptors, genetic polymorphisms (e.g., FCGR3A, NCR3), and viral imprinting (e.g., CMV-induced NKG2C+ memory-like cells) further shape disease-specific outcomes. By comparing shared mechanistic patterns with disease-specific divergences, and integrating evidence from preclinical models, human studies, and recent clinical trials, this chapter elucidates the dynamic, context-dependent roles of NK cells in autoimmunity.