Post-traumatic osteoarthritis (PTOA) is an accelerated form of osteoarthritic cartilage degeneration affecting approximately 20-50% of patients experiencing joint injury. Currently PTOA is incurable; to better understand the etiology of PTOA and to develop rational anti-osteoarthritic therapies, it is critical to understand the spatiotemporal initiation and the progression of PTOA. In this study, we employed semi-quantitative histological scoring and quantitative damage analysis to examine disease progression in the murine destabilization of the medial meniscus (DMM) model of PTOA from early (3 days) through late- (112 days) disease timepoints. We observed significant, progressive articular cartilage (AC) cellular, and structural changes in the medial compartments of injured joints as early as 3 days. Spatially within the joint, cartilage damage (erosions) were observed anteriorly at 84 days. Furthermore, a drastic loss in chondrocyte number (by 3 days), surface damage (at 7 days), and cartilage erosion (at 84 days) was found to co-localize to the specific region of the medial tibial plateau AC that experienced a change in meniscal coverage due to meniscal extrusion following DMM. Taken together, these results suggest that DMM-mediated extrusion of the medial meniscus leads to rapid, spatially dependent changes in AC cellularity and structure, and precipitates the focal degeneration of cartilage associated with PTOA. Importantly, this study suggests that joint instability injuries may trigger immediate (<3 days) processes within a small population of chondrocytes that directs the initiation and progression of PTOA, and that development of chondroprotective strategies for preventing and/or delaying PTOA-related cartilage degeneration are best targeted toward these immediately early processes following joint injury. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:537-547, 2017.