Transforming growth factor-β1 (TGF-β1) can activate mitogen-activated protein kinases (MAPKs) in many types of cells. The mechanism of this activation is not well elucidated. Here, we explore the role of TGF-β/Smads signaling compounds in TGF-β1-mediated activation of extracellular signal-regulated kinase (ERK) MAPK in human papillomavirus (HPV)-18 immortalized human bronchial epithelial cell line BEP2D and the role of TGF-β1-induced phosphorylation of ERK in proliferation and apoptosis of BEP2D.ThecellmodelsofsiRNA-mediatedsilencingofTGF-βreceptortypeII(TβRII),Smad2,Smad3, Smad4,andSmad7wereemployedinthisstudy.OurresultsdemonstratethatTGF-β1activatesERKina time-dependentmannerwithamaximumeffectat60min;overexpressionofSmad7increasedthisTGFβ1-mediatedphosphorylationoftheERK;andsiRNA-mediatedsilencingofTβRII,Smad3,Smad4,and Smad7 abrogated this effect. Moreover, we observed that overexpression of Smad7 restored TGF-β1mediatedERKphosphorylationinSmad4knockdowncellsbutnotinTβRIIknockdowncells.InBEP2D cells,TGF-β1treatmenteffectivelyinhibitedcells’proliferationandinducedtheirapoptosis.Pretreatment with U0126, an inhibitor of ERK1/2, significantly enhanced the TGF-β1-mediated antiproliferative and apoptosis induction effects in BEP2D cells. These data revealed that TβRII and Smad7 play the critical roles in TGF-β1-mediated activation of ERK; Smad3 and Smad4 can play an indirect role through upregulating Smad7 expression; and TGF-β1-induced phosphorylation of ERK may participate in BEP2D cell proliferation and apoptosis regulation.