Objectives: Binding of the bromodomain and extra-terminal domain proteins (BETs) to acetylated histone residues is critical for gene transcription in many fibrotic diseases. This study sought to determine the anti-fibrotic efficacy and potential mechanisms of BET inhibition in scleroderma (SSc). Methods: Dermal fibroblasts were isolated from biopsies from healthy subjects or patients with diffuse cutaneous (dc)SSc. Fibroblasts were treated with pan BET inhibitor JQ1, BRD2 inhibitor BIC1, or BRD4 inhibitors AZD5153 or ARV825. Knockdown of BETs was achieved by siRNA transfection. The in vivo anti-fibrotic efficacy of JQ1 was determined in a bleomycin-induced skin fibrosis mouse model. T-test or ANOVA were used to compare differences between groups, and a p-value of <0.05 was considered significant. Results: BET inhibitor JQ1 dose-dependently downregulated pro-fibrotic genes in dcSSc fibroblasts, and inhibited cell migration and gel contraction. It suppressed proliferation by inducing cell cycle arrest. The anti-fibrotic effects of JQ1 were also observed in TGFβ-treated normal fibroblasts. JQ1 prevented bleomycin-induced skin fibrosis in mice. The anti-fibrotic effect of JQ1 was mediated by inhibition of BRD4, as specific blockade or knockdown of BRD4 led to downregulation of fibrotic markers and inhibition of myofibroblast properties, while inhibition or knockdown of BRD2 or BRD3 had minimal effects in dcSSc fibroblasts. Conclusions: BET inhibition showed promising anti-fibrotic effects in SSc both in vitro and in vivo. Specifically, we showed that BRD4 plays a critical role in SSc fibrosis and that targeting BRD4 might be a novel therapeutic option for this disease.