Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with limited therapeutic options and a poor prognosis. Here, we identify the nuclear receptor NR4A1 as a pivotal mediator of estrogen’s antifibrotic effects through its regulation of TGF-β signaling. Clinical analysis revealed increased expression of NR4A1 and estrogen receptor α (ERα) in IPF lung tissues, with NR4A1 phosphorylation correlating with disease progression. Mechanistic investigations demonstrated that sustained TGF-β signaling induces NR4A1 phosphorylation, impairing its negative feedback regulation of fibrosis. Estrogen, acting via ERα, restored NR4A1 activity by suppressing phosphorylation, thereby reducing fibrosis both in vitro and in vivo. Overexpression of NR4A1 or inhibition of its phosphorylation attenuated fibrotic responses, whereas NR4A1 deficiency abrogated estrogen’s protective effects. These findings elucidate a previously unrecognized mechanism of estrogen-mediated antifibrotic activity and highlight NR4A1 as a promising therapeutic target for IPF.