<p>Keloid is a fibroproliferative skin disease with strong local invasiveness and recurrence. This study investigated the effect of long non-coding RNA H19 overexpression in keloid fibroblast-related growth characteristics and keloid formation. The H19, Smad2, Smad3, Smad7, and transforming growth factor-beta 1 (TGF-β1) expressions in keloid, mature cicatrix, and normal skin tissue of clinical and cell samples were detected by quantitative polymerase chain reaction (qPCR) and immunohistochemistry. H19 overexpression was verified by qPCR. The experimental groups were organized into normal control, lncRNA H19 gene overexpression empty vector, and H19 overexpression groups. Cell proliferation, migration, and invasion were detected by Cell Counting Kit-8, cell scratch test, and Transwell, respectively. A nude mouse keloid model was established. Collagen I, collagen III, H19, Smad2, Smad3, Smad7, and TGF-β1 expressions were detected by immunohistochemistry, qPCR, and Western blot. Compared with normal skin tissue, the lncRNA H19, Smad2, Smad3, and TGF-β1 expressions in keloid and mature cicatrix were significantly increased, whereas Smad7 were significantly decreased (<i>P</i> &lt; 0.05). Compared with mature cicatrix, the lncRNA H19, Smad2, Smad3, and TGF-β1 expressions in keloid were significantly increased, whereas Smad7 were significantly decreased (<i>P</i> &lt; 0.05). Compared with control, the cell proliferation, migration, and invasion in the lncRNA H19 overexpression group increased significantly. Compared with control, the lncRNA H19, collagen I, collagen III, Smad2, Smad3, and TGF-β1 expressions in the lncRNA H19 overexpression group increased significantly, whereas Smad7 decreased significantly (<i>P</i> &lt; 0.05) at the cellular and animal levels. H19 promotes keloid formation by activating Smad2 and Smad3, inhibiting Smad7 expression, and exerting positive feedback on the TGF-β/Smad pathway.</p>