The objective of this study was to develop a novel mouse model to evaluate functional adaptation of the temporomandibular joint to malocclusion. We intended to determine the effect of a mandibular functional shift on the size, shape, and symmetry of the craniofacialskeleton utilizing three-dimensional (3D) semi landmarks and geometrics morphometrics (GM) as well as to analyze histologically the cellular and molecular changes in the temporomandibular joint (TMJ) and in the mandibular condylar cartilage (MCC). A mousemodel of a mandibular functional shift was created by extracting 3 molars from the maxillary right quadrant in FVB/NJ wildtype mice. Teeth were extracted at 3 weeks old, and samples were collected at 6 weeks so that mice developed a functional shift during a maximal growth period from weaning to sexual maturity. The experimental group consisted of 11 mice (5 females and 6 males), and the control group was composed of 10 mice (4 females and 6 males). Micro CT (μCT) was performed on the entire heads of experimental and control mice. The TMJs on both the extraction and non-extraction sides in the experimental animals were compared to the control (with no teeth extracted) for the following variables: (1) geometric morphometric analysis of the size and shape of craniofacial skeleton, including the cranium, cranial base, maxilla, and mandible; (2) changes in bone volume and density of the TMJ condyle were determined using the μCTdata, and (3) the TMJ and MCC were analyzed histologically and by in situ hybridization for specific markers. Overall, the size and shape of the cranial skeleton was not affected in the extraction model; however, there were changes in the mandibular shape. In the mandible, the molar alveolus height was increased on the extraction side compared to non-extraction and control. The condylar head and neck width were narrower, and the superior surface of the condylar head was more convex on both the extraction side andthe non-extraction side in the experimental animals compared tocontrols. Furthermore, the bone volume of the condylar process on both the extraction side and the nonextraction side in the experimental animals was decreased by 15%, and the bone densitywas increased by 5% compared to condyles from control animals. Finally, the MCC was thinner in both the extraction and non-extraction sides in the experimental group, and the expression of Col2 and Col10 was increased, suggesting an expansion in maturationstage and hypertrophic chondrocytes, and there was ectopic expression of Col1 in the MCC, suggesting a pro-osteogenic response in the extraction condyle samples compared to controls.Our results suggest extraction of the molars in one quadrant in our mouse model resulted in a presumed shift in the mandible and degenerative adaptations in the condylar shape. There was loss of bone volume in the condylar process and apparent depositionof bone with increased mineral density near the condylar head surface in both condyles of the extraction mice compared to controls. At the cellular level, there was an increase in maturation stage and hypertrophic chondrocytes and osteoblasts in the MCC that mayhave contributed to the remodeling and bone deposition at the condylar surface. This phenotype is suggestive of osteoarthritic changes in that thinning of the MCC and increased bone deposition at the condylar surface was observed. These data further elucidate the tissue and cellular changes in the condyle due to a functional shift, which furthers our understanding of the pathology of this malocclusion.