House endotoxin and ambient air pollution are risk factors for asthma; however, the effects of their co-exposure on asthma are not well characterized. Objectives: To examine potential synergistic associations of co-exposure to house dust endotoxin and ambient air pollutants with asthma outcomes. Methods: We analyzed data from 6,488 participants in National Health and Nutrition Examination Survey (NHANES) 2005-2006. Dust from bedding and bedroom floor was analyzed for endotoxin content. The Community Multiscale Air Quality (CMAQ) and Downscaler (DS) data were used to determine annual average particulate matter ≤2.5 μm (PM_2.5), ozone (O₃), and nitrogen dioxide (NO₂) exposures at participants’ residential locations. The associations of the co-exposures with asthma outcomes were assessed and tested for synergistic interaction. Results: In adjusted analysis, PM_2.5 (CMAQ) (OR 1.12, 95% CI: 1.07-1.18), O₃ (DS) (OR 1.07, 95% CI: 1.02-1.13), and log₁₀10-NO₂ (CMAQ) (OR 3.15, 95% CI: 1.33-7.45) were positively associated with emergency room (ER) visits for asthma in the past 12 months. Co-exposure to elevated levels of house dust endotoxin and PM_2.5 (CMAQ) was synergistically associated with the outcome, increasing the odds by 5-fold (OR 5.01, 95% CI: 2.54-9.87). A synergistic association was also found for co-exposure to higher concentrations of endotoxin and NO₂ in children (OR 3.45, 95% CI: 1.65-7.18). Conclusions: Co-exposure to elevated levels of residential endotoxin and ambient PM_2.5 in all participants and NO₂ in children is synergistically associated with increased ER visits for asthma. Therefore, decreasing exposure to both endotoxin and air pollution may help reduce asthma morbidity.