Microfracture does not properly repair full-thickness cartilage defects. The purpose of this study was to evaluate the effect of intraarticular injection of the small-molecule compound kartogenin (KGN) on the restoration of a full-thickness cartilage defect treated with microfracture in a rabbit model. Full-thickness cartilage defects (3.5 mm in diameter and 3 mm in depth) were created in the patellar groove of the right femurs of 24 female New Zealand White rabbits. The rabbits were divided into two groups (12 in each group) based on postsurgery treatment differences, as follows: microfracture plus weekly intraarticular injection of KGN (group 1) and microfracture plus dimethyl sulfoxide (group 2). Six rabbits from each group were illed at 4 and 12 weeks after surgery, and their knees were harvested. The outcome was assessed both macroscopically, by using the International Cartilage Repair Society (ICRS) macroscopic evaluation system, and histologically, by using the modified O'Driscoll histologic scoring system. Immunohistochemistry for type II and I collagen was also conducted. At 4 weeks, group 1 showed better defect filling and a greater number of chondrocyte-like cells compared with group 2. At 12 weeks, group 1 showed statistically significantly higher ICRS scores and modified O'Driscoll scores compared with group 2. More hyaline cartilage-like tissue was found in the defects of group 1 at 12 weeks. Intraarticular injection of KGN enhances the quality of full-thickness cartilage defects repair after microfracture, with better defect filling and increased hyaline-like cartilage formation.