Chikungunya virus (CHIKV) belongs to alphavirus infections which often tend to deliberate musculoskeletal disorders affecting joints, muscles, and bones. Primary cells isolated from patients undergoing total knee replacement were utilized to perceive the effect of virus infection on it, upon isolation and characterization. A well-characterized set of cells was utilized to set the model system in a 2D monolayer and a 3D spheroidal model which was used to evaluate the infection profile of primary chondrocyte cells to CHIKV, the model systems were infected at different multiplicity of infection (MOI) of 0.1, 1 over number of days. Viral titers were determined by plaque assay. We further obtained the global proteome of the infected chondrocytes in its 2D and 3D architecture and analysed various pathways and perturbed proteins in two model systems. Gene expression studies were conducted using total RNA of isolated from cells to study the articular genes upon infection. Our study demonstrates that human chondrocyte cells are permissive to CHIKV infection which is evaluated in both 2D model system and 3D model systems, a comparative study of the proteomes of the chondrocytes was obtained from both 2D and 3D cultures in which distinct protein signatures attributing to cell architecture and immune system were detected.