To investigate the role of a disintegrin and metalloprotease protein 17 (ADAM17) in regulating the proliferation and extracellular matrix (ECM) expression of keloid fibroblasts (KFs) via the epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinase (ERK) pathway. ADAM17 expression in keloid tissues was detected by western blotting. KFs were isolated, cultured and divided into the control, shNC (negative control), shADAM17, transforming growth factor-β1 (TGF-β1), TGF-β1 + shNC and TGF-β1 + shADAM17 groups. The expression of ECM was detected by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Western blotting was performed to detect the expression of proteins. Cell proliferation was detected by a 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay, while cell invasion and migration were examined by Transwell and wound healing assays. The expression of ADAM17 was increased in keloid tissues and KFs. Compared with the control group, the expression of p-EGFR and p-ERK/1/2/ERK1/2, as well as the expression of collagen I, collagen III, connective tissue growth factor (CTGF) and α-smooth muscle actin (α-SMA), were decreased in KFs from the shADAM17 group, with decreased cell proliferation, invasion and migration. In contrast, the TGF-β1 group presented the opposite trend in these aspects. In addition, compared with the TGF-β1 group, KFs from the TGF-β1 + shADAM17 group had decreased ECM expression, proliferation, invasion and migration. ADAM17 expression was upregulated in keloid tissues. Silencing ADAM17 may inhibit the activity of the EGFR/ERK pathway to limit the deposition of ECM in KFs with reduced proliferation, invasion and migration.