Idiopathic pulmonary fibrosis is a progressive and fatal interstitial lung disease with a poor prognosis and limited therapeutic options, which is characterized by aberrant myofibroblast activation and pathological remodeling of the extracellular matrix, while the mechanism remains elusive. In the present investigation, we observed a reduction in ADRB2 expression within both IPF and bleomycin-induced fibrotic lung samples, as well as in fibroblasts treated with TGF-β1. ADRB2 inhibition blunted bleomycin-induced lung fibrosis. Blockage of the ADRB2 suppressed proliferation, migration, and invasion and attenuated TGF-β1-induced fibroblast activation. Conversely, the enhancement of ADRB2 expression or functionality proved capable of inducing fibroblast-to-myofibroblast differentiation. Subsequent mechanistic investigation revealed that inhibition of ADRB2 suppressed the activation of SMAD2/3 in lung fibroblasts and increased phos-SMAD2/3 proteasome degradation, and vice versa. Finally, ADRB2 inhibition combined with antioxidants showed increased efficacy in the therapy of bleomycin-induced lung fibrosis. In short, these data indicate that ADRB2 is involved in lung fibroblast differentiation, and targeting ADRB2 could emerge as a promising and innovative therapeutic approach for pulmonary fibrosis.