Introduction The aim was to investigate the effect of collagen sponges (CS) as a delivery device for osteoprotegerin (OPG)/bone morphogenetic protein 2 (BMP-2) and support matrix on the tendon-bone healing after anterior crusicate ligament (ACL) reconstruction in modeled rabbits. Materials and Methods Sixty New Zealand white rabbits were randomly divided into four groups based on treatments they received at the tendon-bone interface after left knee ACL reconstruction: the control group, OPG/BMP-2, CS, and OPG/BMP-2/CS combination. At 4, 8 and 12 weeks post-surgery, five rabbits from each group were euthanized to examine the tendon-bone healing. Levels of OPG and BMP-2 in synovial fluid, the bone tunnel enlargement value, the histomorphological typing of tendon-bone interface, and the bone tunnel area of the tendon-bone interface were compared among different treatments. Results The OPG/BMP-2/CS combination treatment group had the highest levels of OPG and BMP-2 in synovial fluid (both P  < 0.05), the greatest number of Sharpey-like collagen fibers at all test points ( P  < 0.05), the most fibrocartilage enthesis on week 12, the greatest bone tunnel area ( P  < 0.05), and the greatest decrease in bone tunnel enlargement on week 12 ( P  < 0.05). Histomorphological typing of tendon-bone interface of all groups showed changes varying from tendon-bone separation to firm healing, and the change was most significant in the OPG/BMP-2/CS combination treatment group. Conclusion CS treatment alone serves as a fixing support, and CS combining with growth factors OPG/BMP-2 ensures slow and stable release of OPG/BMP-2, significantly improves the tendon-bone healing in the rabbit ACL model.