The clinical management of asthma involves treatment with inhaled corticosteroids (ICS) and long-acting β2-adrenoceptor agonists (LABAs). Regulator of G-protein signalling (RGS) 2 inhibits signalling from Gq protein-coupled receptors. In humans, combinations of a glucocorticoid and a LABA synergistically enhanced the expression of RGS2. In mice, 3 weeks of HDM challenge or 30 min of LPS challenge reduced lung function and induced airways inflammation. Compared to wild-type, Rgs2-/- mice showed significantly increased airways resistance and reduced compliance, in both HDM- and LPS-challenges. There was no difference between wild-type and Rgs2-/- mice in HDM-induced and LPS-induced inflammation. There was a trend towards increased inflammatory cell counts in the BALF of Rgs2-/- compared to wild-type. There was a trend towards increased expression for many HDM-induced cytokines/chemokines in Rgs2-/-. There was no difference between wild-type and Rgs2-/- mice in LPS-induced expression of cytokines/chemokines. These data show Rgs2 is bronchoprotective in HDM-induced inflammation and suggest a modest anti-inflammatory role. Rgs2 is bronchoprotective in LPS-induced inflammation, but more studies are required to address a possible anti-inflammatory role. If applicable to humans, these data suggest that therapeutics, for example ICS/LABA combination therapies, which are designed to maximize RGS2 expression, will be beneficial for asthma control and management.