For the successful commercial development of emerging 2D materials, it is crucial to understand their potential biological effects on healthy and diseased individuals. The present study demonstrates that a repeated low‐dose (1 µg cm −2 for 5 weeks) exposure of primary human broncho‐epithelial (HBE) cell cultures to hexagonal boron nitride nanosheets ( h ‐BN) and boron nitride nanotubes (BNNTs) increases the phospholipid, sphingolipid, and diglyceride content in cell membranes. Global lipidomics profiling further shows the induction of lipid mediator biosynthesis, especially after exposure to BNNTs in asthmatic cell cultures. The significant increase in leukotriene biosynthesis including its extracellular release is also confirmed in vivo in exposed mouse lungs. Mechanistically, extracellular release of lipid mediators prompts the recruitment and activation of immune cells. Mass cytometry‐based single‐cell profiling of human peripheral blood mononuclear cells reveals the activation of distinct lymphocyte populations expressing cytotoxic granzyme B and perforin mainly after exposure to conditioned medium from BNNT‐exposed asthmatic HBE cultures. These findings unveil the sub‐cytotoxic impact of BN nanomaterials on cellular lipid homeostasis and associated immunomodulation from repeated‐dose exposures, which may pose a potential health hazard, particularly for immune‐compromised individuals, and therefore, needs to be considered for the responsible and sustainable production and use of BN‐based products.