M2 macrophages (M2 cells) are known to be involved in both Th2 responses and immune regulation. However, the underlying mechanisms remain unclear. Functional abnormalities in macrophages are associated with airway allergy (AA). The objective of this study was to investigate the role of methyltransferase-like 5 (Mettl5) in macrophages and its potential to alleviate AA. In this study, an airway allergy (AA) mouse model was established using dust mite extracts (DME) as the specific antigen. M2 cells were collected from mice with and without AA. The role of Mettl5 in modulating the immune activities of M2 cells was assessed using both epigenetic and immunological approaches. We found that Mettl5 levels were elevated in airway M2 cells from mice with AA. The presence of Mettl5 in airway M2 cells was positively correlated with airway Th2 polarization in these mice. Airway M2 cells from AA mice exhibited impaired immune-suppressive function, which was resolved by ablating the Mettl5 gene in macrophages. Mettl5 was responsible for the hypermethylation of the Il10 promoter in airway M2 cells of AA mice. Exposure to DME induced Mettl5, which in turn recruited USP21 to deubiquitinate GATA3, thereby boosting IL-4 expression in M2 cells. Inhibiting Mettl5 restored the immune-suppressive capacity of airway M2 cells and mitigated experimental AA. In conclusion, Mettl5 plays a critical role in subverting the immune-regulatory capacity and enhancing IL-4 expression in M2 cells. Inhibition of Mettl5 can mitigate experimental AA by restoring the immune-regulatory functions of M2 cells.