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Background: Hypertrophic scars (HSs) cause functional impairment and cosmetic deformities following operations or burns (30% to 94%). There is no target therapy yet because the pathogenesis of HS progression is not well known. In tissue fibrosis, abnormal up-regulation of zinc finger E-box binding homeobox 1 (ZEB1) is an important cause for extracellular matrix (ECM) overexpression, which is the main molecular change in HSs. The authors hypothesized that ZEB1 knockdown inhibits HS formation., Methods: ZEB1 expression in human HS and transforming growth factor-β1-induced fibroblasts were identified by polymerase chain reaction (PCR) and Western blotting. ZEB1 was knocked down by small interfering RNA in HS fibroblasts (HSFs) and the mouse HS model (C57/BL6 male mice aged 8 to 12 weeks). After 8 hours of transfection, HSFs were subjected to PCR, Western blotting, and Cell Counting Kit-8 apoptosis, migration, and contraction assays. Mouse HSs were analyzed by hematoxylin and eosin staining, PCR, and Western blotting after 56 days., Results: ZEB1 was up-regulated in HS tissue (2.0-fold; P < 0.001). ZEB1 knockdown inhibited HSF activity (0.6-fold to 0.7-fold; P < 0.001); the expression of fibrotic markers (0.4-fold to 0.6-fold; P < 0.001); and β-catenin, cyclinD1, and c-Myc expression (0.5-fold; P < 0.001). In mouse HS models, HS skin thickness was less (1.60 ± 0.40 mm versus 4.04 ± 0.36 mm; P < 0.001) after ZEB1 knockdown., Conclusions: ZEB1 knockdown inhibits HS formation both in vitro and in vivo. However, this is an in vitro mouse model, and more validation is needed., Clinical Relevance Statement: The discovery of ZEB1 as a mediator of HS formation might be a potential therapeutic target in HS treatment., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Plastic Surgeons.)