In order to investigate the role which sirtuin-6 (SIRT6) plays in lumbar spinal epidural fibrosis (EF) and scar formation in vitro and in vivo， SIRT6 and transforming growth factor β (TGF‑β) protein levels in the lumbar disc of patients were detected using western blotting in patients who had undergone a laminectomy. The results demonstrated that SIRT6 expression was significantly reduced in the lumbar discs of patients in whom an epidural scar had formed， but the expression pattern of TGF-β2 was much higher. Subsequently， a pcDNA‑SIRT6 expression vector was constructed and transfected into the primary fibroblasts isolated from the epidural scars. Flow cytometric and MTT analyses indicated that overexpression of SIRT6 suppressed the proliferation of the fibroblasts， and TGF‑β2 and interleukin-1α expression， as well as collagen type I (Col I) production. The results of bioinformatics and molecular biological analyses demonstarted that TGF‑β2 was a target of microRNA-21 (miR-21) and SIRT6 overexpression suppressed the levels of TGF-β2 through promoting the expression of miR-21. Finally， by injecting the pcDNA-SIRT6 vector， it was possible to observe that SIRT6 suppressed EF and epidural scar formation in vivo. In conclusion， we noted that SIRT6 suppressed EF and epidural scar formation in vitro and in vivo. It was also noted that SIRT6 overexpression suppressed TGF-β2 levels by promoting the expression of miR-21.