Background:　Systemic　sclerosis　(SSc;　also　known　as　“scleroderma”)　is　an　autoimmune　disorder　characterized　by　extensive　fibrosis,　vascular　changes,　and　immunologic　dysregulation.　Baicalein　(phenolic　flavonoid　derived　from　Scutellaria　baicalensis　Georgi)　has　been　used　to　treat　the　pathological　processes　of　various　fibrotic　and　inflammatory　diseases.　In　this　study,　we　investigated　the　effect　of　baicalein　on　the　major　pathologic　characteristics　of　SSc:　fibrosis,　B-cell　abnormalities,　and　inflammation.　Methods:　The　effect　of　baicalein　on　collagen　accumulation　and　expression　of　fibrogenic　markers　in　human　dermal　fibroblasts　were　analyzed.　SSc　mice　were　produced　by　injecting　bleomycin　and　treated　with　baicalein　(25,　50,　or　100 mg/kg).　The　antifibrotic　features　of　baicalein　and　its　mechanisms　were　investigated　by　histologic　examination,　hydroxyproline　assay,　enzyme-linked　immunosorbent　assay,　western　blotting　and　flow　cytometry.　Results:　Baicalein　(5–120 μM)　significantly　inhibited　the　accumulation　of　the　extracellular　matrix　and　fibroblast　activation　in　transforming　growth　factor　(TGF)-β1-　and　platelet　derived　growth　factor　(PDGF)-induced　human　dermal　fibroblasts,　as　evidenced　by　abrogated　deposition　of　total　collagen,　decreased　secretion　of　soluble　collagen,　reduced　collagen　contraction　capability　and　downregulation　of　various　fibrogenesis　molecules.　In　a　bleomycin-induced　model　of　dermal　fibrosis　in　mice,　baicalein　(25–100 mg/kg)　restored　dermal　architecture,　ameliorated　inflammatory　infiltrates,　and　attenuated　dermal　thickness　and　collagen　accumulation　in　a　dose-dependent　manner.　According　to　flow　cytometry,　baicalein　reduced　the　proportion　of　B　cells　(B220+　lymphocytes)　and　increased　the　proportion　of　memory　B　cells　(B220+CD27+　lymphocytes)　in　the　spleens　of　bleomycin-induced　mice.　Baicalein　treatment　potently　attenuated　serum　levels　of　cytokines　(interleukin　(IL)-1β,　IL-2,　IL-4,　IL-6,　IL-17A,　tumor　necrosis　factor-α),　chemokines　(monocyte　chemoattractant　protein-1,　macrophage　inflammatory　protein-1　beta)　and　autoantibodies　(anti-scleroderma　70　(Scl-70),　anti-polymyositis-scleroderma　(PM-Scl),　anti-centromeres,　anti-double　stranded　DNA　(dsDNA).　In　addition,　baicalein　treatment　can　significantly　inhibit　the　activation　of　TGF-β1　signaling　in　dermal　fibroblasts　and　bleomycin-induce　mice　of　SSc,　evidenced　by　reducing　the　expression　of　TGF-β1　and　IL-11,　as　well　as　inhibiting　both　small　mother　against　decapentaplegic　homolog　3　(SMAD3)　and　extracellular　signal-related　kinase　(ERK)　activation.　Conclusions:　These　findings　suggest　that　baicalein　has　therapeutic　potential　against　SSc,　exerting　modulating　B-cell　abnormalities,　anti-inflammatory　effects,　and　antifibrosis.　©　2023,　The　Author(s).