A recent study demonstrated a significant role for leukotriene B₄ (LTB₄) causing pulmonary vascular remodeling in pulmonary arterial hypertension. LTB₄ was found to directly injure luminal endothelial cells and promote growth of the smooth muscle cell layer of pulmonary arterioles. The purpose of this study was to determine the effects of LTB₄ on the pulmonary adventitial layer, largely composed of fibroblasts. Here, we demonstrate that LTB₄ enhanced human pulmonary artery adventitial fibroblast proliferation, migration, and differentiation in a dose-dependent manner through its cognate G-protein–coupled receptor, BLT1. LTB₄ activated human pulmonary artery adventitial fibroblast by upregulating p38 mitogen-activated protein kinase as well as Nox4-signaling pathways. In an autoimmune model of pulmonary hypertension, inhibition of these pathways blocked perivascular inflammation, decreased Nox4 expression, reduced reactive oxygen species production, reversed arteriolar adventitial fibroblast activation, and attenuated pulmonary hypertension development. This study uncovers a novel mechanism by which LTB₄ further promotes pulmonary arterial hypertension pathogenesis, beyond its established effects on endothelial and smooth muscle cells, by activating adventitial fibroblasts.