The ${eta}_2$ adrenergic receptor (ADRB2) is a G protein-coupled transmembrane receptor expressed in the human respiratory tract and widely recognized as a pharmacological target for treatments of asthma and chronic obstructive pulmonary disorder (COPD). Although a number of ADRB2 agonists have been developed for use in asthma therapy, indacaterol is the only ultra-long-acting inhaled ${eta}_2$-agonist (LABA) approved by the FDA for relieving the symptoms in COPD patients. The precise molecular mechanism underlying the pharmacological effect of indacaterol, however, remains unclear. Here, we show that ${eta}$-arrestin-2 mediates the internalization of ADRB2 following indacaterol treatment. Moreover, we demonstrate that indacaterol significantly inhibits tumor necrosis factor-${alpha}$ (TNF-${alpha}$)-induced NF-${kappa}B$ activity by reducing levels of both phosphorylated-IKK and -$I{kappa}B{alpha}$, thereby decreasing NF-${kappa}B$ nuclear translocation and the expression of MMP-9, an NF-${kappa}B$ target gene. Subsequently, we show that indacaterol significantly inhibits TNF-${alpha}$/NF-${kappa}B$-induced cell invasiveness and migration in a human cancer cell line. In conclusion, we propose that indacaterol may inhibit NF-${kappa}B$ activity in a ${eta}$-arrestin2-dependent manner, preventing further lung damage and improving lung function in COPD patients.