Medial meniscus destabilization (MMD) is a surgical insult technique for modeling osteoarthritis (OA) by replicating chronic abnormal cartilage loading in animal joints in vivo. The present study aimed to characterize the immediate biomechanical effects (ex vivo) and short-term histological consequences (in vivo) of MMD in the rabbit knee. In a compressive loading test, contact stress distribution in the medial compartment was measured in eight cadaver rabbit knees, initially with all major joint structures uninjured (Baseline), after MMD, and finally after total medial meniscectomy (TMM). Similarly, the effects on sagittal joint stability were determined in an anterior-posterior drawer test. These biomechanical (ex vivo) data indicated that both MMD and TMM caused significant (p < 0.001), distinct (>1.5-fold) elevation of peak local contact stress in the medial compartment, while leaving whole-joint stability nearly unchanged. Histological consequences in vivo were assessed in a short-term (8-week) survival series of MMD or TMM (five animals for each group), and both caused moderate cartilage degeneration in the medial compartment. The MMD insult, which is feasible through posterior arthrotomy alone, is as effective as TMM for modeling injurious-level chronic abnormal cartilage loading in the rabbit knee medial compartment in vivo, while minimizing potential confounding effects from whole-joint instability. Copyright © 2013 Orthopaedic Research Society.