Objective: To investigate the effects of everolimus (EVE) on postoperative fibrosis in the knee joint and the potentially relevant signaling pathways. Methods: CCK-8 and flow cytometry assays were used to detect the effect of EVE on human fibroblast viability and apoptosis induction. IF and TEM were used to assess fibroblast autophagy. 3-methyladenine (3-MA) was applied to inhibit autophagy to clarify the relationship between autophagy and apoptosis. WB was used to measure the expression of proteins related to apoptosis, autophagy and the mTOR signaling pathway. A rabbit model of knee joint fibrosis was established and topically treated with various concentrations of EVE. IF-P was applied to identify that the main components cells of the fibrotic tissue and histomorphological staining was used to detect the degree of fibrosis and the content of collagen. Results: Histomorphological staining demonstrated that EVE could reduce the degree of postoperative fibrosis and collagen deposition in the knee joint. The results of IF, TEM, flow cytometry assays and WB detection showed that EVE could activate autophagy and induce fibroblasts apoptosis. Meanwhile, the expression levels of p-PI3K, p-Akt, p-mTOR were downregulated with EVE treatment. After the inhibition of autophagy by 3-MA treatment, the increased fibroblasts apoptosis by EVE treatment was partially decreased. Conclusion: Everolimus can reduce surgery-induced knee fibrosis by inducing autophagy-mediated fibroblast apoptosis, which may be involved with the regulation of the PI3K/Akt/mTOR signaling pathway. (C) 2020 Elsevier Inc. All rights reserved.