Significance Perfluoroalkyl chemicals (PFCs) are man-made chemicals ubiquitously present in humans. We demonstrate that a major PFC, perfluorooctane sulfonate (PFOS), dampens mice from developing house dust mite (HDM)–induced asthma, while abolishing the microbial product LPS’s protective effect in asthma development. This finding has direct human relevance, considering the low-PFOS concentrations necessary for its effect. Mechanistically, PFOS binds with high affinity to Der p1, a major allergen from HDM, as well as to the lipid A moiety of LPS, resulting in their inactivation. Our data highlight that PFC exposure may play a previously unappreciated role in modulating allergic asthma and emphasize the importance of reducing exposure.