Endometriosis is one of the most common, difficult, and complicated gynecological disorders. The present study investigated the expression of HOXC6 in endometriosis and described its possible role in its pathogenesis. Ectopic and eutopic endometrial samples from 21 patients with endometriosis and a control endometrium from 15 women without endometriosis were collected. HOXC6 expression in endometrial tissue was analyzed with immunohistochemistry and quantitative reverse transcription polymerase chain reaction. HOXC6's silencing in endometriotic stromal cells (ESC) was established with small interfering RNA (siRNA) to detect the effect on proliferation, adhension, invasion, and migration using CCK-8, adhesion, wound healing, and transwell assays. Western blotting was performed to detect the expression of related molecules after the down-regulation of HOXC6. HOXC6 mRNA and protein expression levels in the ectopic endometrial samples were significantly higher in women with endometriosis than in controls, while the levels in the eutopic endometrial tissues of the same patients did not significantly differ from those in non-endometriotic patients. The knockdown of HOXC6 expression inhibited the proliferation, adhesion, migration, and invasion of ESC. The results indicated that HOXC6 down-expression decreased the expression of N-cadherin and vimentin, whereas the expression of E-cadherin increased. HOXC6 down-expression also decreased the expression levels of TGF-β1 and phosphorylated SMAD2/SMAD3. In conclusion, HOXC6 was overexpressed in endometriosis and might therefore promote the proliferation, adhesion, invasion, and migration of ESC via the TGF-β1/smad signaling pathway. These findings present a new perspective and may therefore inspire further study of the endometriosis mechanism.