Objective <p>Hypertrophic scars (HS) are the result of abnormal tissue repair after dermal tissue trauma. Their histological characteristics are fibroblast proliferation and excessive deposition of extracellular matrix. This study aimed to identify the role of autologous fat granule (AFG) combined with platelet-rich plasma (PRP) in HS formation and its possible mechanism through in vivo experiments.</p> Methods <p>A rat wound healing HS model was established, and AFG and PRP alone or in combination treated HS model rats. After 8&#xa0;weeks of intervention, HS tissues were collected for HE staining, VG staining, immunohistochemistry, ELISA and Western blot analysis.</p> Results <p>AFG treatment could significantly inhibit angiogenesis and hypertrophic scar proliferation in HS tissue, and reduce collagen fiber content and inflammatory cell infiltration, and the above changes were more significant when combined with PRP treatment, indicating that AFG combined with PRP treatment had a better therapeutic effect in HS animal model. In addition, AFG treatment can significantly reduce the expression of TGFBRI and Smad3 proteins in HS tissues, and compared with AFG alone, AFG combined with PRP treatment can further reduce the expression of TGFBRI and Smad3 proteins in HS tissues.</p> Conclusion <p>AFG combined with PRP can reduce inflammatory cell infiltration and collagen fiber content in HS tissue, and inhibit angiogenesis and scar proliferation, which may be related to inhibiting the activation of TGF-β/Smad signaling pathway. Our study provides a reference for the clinical treatment of HS.</p> No Level Assigned <p>No level of evidence is needed for Basic Science, Animal Study, and Experimental Study Articles. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors <a href="http://www.springer.com/00266">www.springer.com/00266</a>.</p>