Uncontrolled activation of the coagulation cascade after tissue injury has been implicated in both inflammation and tissue fibrosis. Thrombin exerts pluripotent cellular effects via its high-affinity receptor, proteinase-activated receptor-1 (PAR₁) and signaling via Gα_i/o, Gα_q, or Gα_12/13. Activation of PAR₁ on fibroblasts, a key effector cell in fibrosis, results in the induction of several mediators, including the potent monocyte and fibrocyte chemoattractant CCL2. The aim of this study was to identify the G protein and signaling pathway involved in PAR₁-mediated CCL2 production and release. Using a novel PAR₁ antagonist that blocks the interaction between PAR₁ and Gα_q, we report for the first time that PAR₁ coupling to Gα_q is essential for thrombin-induced CCL2 gene expression and protein release in murine lung fibroblasts. We further demonstrate that these effects are mediated via the cooperation between ERK1/2 and Rho kinase signaling pathways: a calcium-independent protein kinase C (PKC), c-Raf, and ERK1/2 pathway was found to mediate PAR₁-induced CCL2 gene transcription, whereas a phospholipase C, calcium-dependent PKC, and Rho kinase pathway influences CCL2 protein release. We propose that targeting the interaction between PAR₁ and Gα_q may allow us to selectively interfere with PAR₁ proinflammatory and profibrotic signaling, while preserving the essential role of other PAR₁-mediated cellular responses.