Asthma is a multifactorial disease that is influenced by the interaction of genetic and environmental factors. Because of its complex nature, there is no cure for asthma currently. Instead, reliever and controller medications are used to treat asthma. Unfortunately, conventional treatments do not work in some severe cases of asthma. In addition, there may be adverse, systemic effects of long-term treatment with high-dose inhaled corticosteroids (ICSs) as a controller medication. Therefore, we attempted to develop a novel combination therapy for asthma. Our regimen included dexamethasone as a controller medication and vitamin D binding protein (VDBP) small interfering RNA (siRNA) as a novel target therapeutic. The dexamethasone moiety of DEXA-PEI (dexamethasone-conjugated polyethylenimine) was used as an ICS, combined with anti-VDBP treatment via delivery of VDBP siRNA, using DEXA-PEI as a siRNA carrier molecule. Treatment with DEXA-PEI/VDBP siRNA effectively reduced the ovalbumin sensitization/challenge-induced enhancement of airway inflammation, goblet cell hyperplasia and expression of interleukin (IL)-4, IL-13 and CCL11. These findings suggest that the DEXA-PEI/VDBP siRNA can be developed as a potent asthma therapeutic by dose-reducing ICSs and using a multitarget therapeutic method.