Objective—To determine expression of collagenolytic genes and collagen degradation in stifle tissues of dogs with ruptured cranial cruciate ligament (CCL).Animals—Six dogs with CCL rupture and 11 dogs with intact CCL.Procedures—Gene expression in CCL tissue and synovial fluid cells was studied using reverse transcriptase‐polymerase chain reaction (RT‐PCR). Collagen degradation was studied using CCL explant cultures and a synovial fluid bioassay.Results—Expression of matrix metalloproteases (MMP) was not found in young Beagles with intact CCL; however, increased expression of MMP‐3 was found in CCL tissue from older hounds with intact CCL, when compared with young Beagles. In dogs with ruptured CCL, expression of MMP‐2 and ‐9 was increased in stifle tissues, when compared with dogs with intact CCL. Similar to MMP‐9, expression of tartrate‐resistant acid phospatase (TRAP) and cathepsin S was only found in stifle tissues from dogs with ruptured CCL; in contrast, expression of cathepsin K was found in all ruptured and intact CCL. Collagen degradation was increased in ruptured CCL, when compared with intact CCL.Conclusion—Rupture of the CCL is associated with up‐regulation of expression of MMP‐2 and ‐9 (gelatinase A and B), TRAP, and cathepsin S, and increased degradation of collagen.Clinical Relevance—These findings suggest that MMP‐2, ‐9, cathepsin S, and TRAP may be important mediators of progressive joint destruction in dogs with CCL rupture. These genes are markers for macrophages and dendritic cells. MMP and cathepsin S pathways may offer novel targets for anti‐inflammatory medical therapy aimed at ameliorating joint degradation associated with inflammatory arthritis.