This study investigated articular cartilage (AC) homeostasis and different signaling pathways involved in the superior cartilage regeneration of Murphy Roths large (MRL/MpJ) mice previously reported. We collected uninjured and destabilized medial meniscus (DMM)‐injured knees from 8‐wk‐old C57BL/6J and MRL/MpJ mice. We used micro‐computed tomography (microCT), histology, and immunohistochemistry to evaluate AC homeostasis and repair. We used the ear punch model to investigate the role of angiogenesis and inflammation in the superior healing of MRL/MpJ mice. We found fewer β‐catenin and more pSMAD5 positive cells in the uninjured AC of MRL/MpJ mice than that from C57BL/6J mice. MRL/MpJ mice exhibited better AC repair in DMM‐induced OA, as indicated by microCT results, Alcian blue, and Safranin O staining. Mechanistically, fewer β‐catenin, pSMAD2‐, pSMAD3‐, a disintegrin and metalloproteinase with thrombospondin motifs 4–, matrix metalloproteinase (MMP) 9–, and MMP13‐positive cells and more proliferating cell nuclear antigen—and pSMAD5‐positive cells were found in the DMM‐injured AC in MRL/MpJ mice than in normal mice. The accelerated ear wound healing of MRL/MpJ mice correlated with enhanced angiogenesis and macrophage polarization toward the M2a phenotype through elevated IL‐10 and IL‐4 expressing cells. Collectively, our study revealed that down‐regulation of pSMAD2/3, β‐catenin, and MMPs and up‐regulation of pSMAD5 and M2a macrophage polarization contribute to the enhanced cartilage repair observed in MRL/MpJ mice.—Deng, Z., Gao, X., Sun, X., Amra, S., Lu, A., Cui, Y., Eltzschig, H. K., Lei, G., Huard, J. Characterization of articular cartilage homeostasis and the mechanism of superior cartilage regeneration of MRL/MpJ mice. FASEB J. 33, 8809–8821 (2019). www.fasebj.org