Meniscectomy is a significant risk factor for osteoarthritis, involving altered cell synthesis, central fibrillation, and peripheral osteophyte formation. Though changes in articular cartilage contact pressure are known, changes in tissue-level mechanical parameters within articular cartilage are not well understood. Recent imaging research has revealed the effects of meniscectomy on the time-dependent deformation of physiologically loaded articular cartilage. To determine tissue-level cartilage mechanics that underlie observed deformation, a novel finite element modeling approach using imaging data and a contacting indenter boundary condition was developed. The indenter method reproduces observed articular surface deformation and avoids assumptions about tangential stretching. Comparison of results from an indenter model with a traditional femur–tibia model verified the method, giving errors in displacement, solid and fluid stress, and strain below 1% (RMS) and 7% (max.) of the absolute maximum of the parameters of interest. Indenter finite element models using real joint image data showed increased fluid pressure, fluid exudation, loss of fluid load support, and increased tensile strains centrally on the tibial condyle after meniscectomy—patterns corresponding to clinical observations of cartilage matrix damage and fibrillation. Peripherally there was decreased consolidation, which corresponds to reduced contact and fluid pressure in this analysis. Clinically, these areas have exhibited advance of the subchondral growth front, biological destruction of the cartilage matrix, cartilage thinning, and eventual replacement of the cartilage via endochondral ossification. Characterizing the changes in cartilage mechanics with meniscectomy and correspondence with observed tissue-level effects may help elucidate the etiology of joint-level degradation seen in osteoarthritis.