The core-shell structured PS/SiO composite nanospheres were synthesized on the basis of a modified Stöber method. The mechanical properties of monodisperse nanospheres were characterized with nanoindentation on the basis of the atomic force microscopy (AFM). The surface morphologies of PS/SiO composite nanospheres was scanned with the tapping mode of AFM, and the force-distance curves were measured with the contact mode of AFM. Different contact models were compared for the analyses of experimental data. The elastic moduli of PS/SiO composite nanosphere (4-40 GPa) and PS nanosphere (∼3.4 GPa) were obtained with the Hertz and Johnson-Kendall-Roberts (JKR) models, respectively, and the JKR model was proven to be more appropriate for calculating the elastic modulus of PS/SiO nanospheres. The elastic modulus of SiO shell gradually approached a constant value (∼46 GPa) with the increase of SiO shell thickness. A core-shell model was proposed for describing the relationship between PS/SiO composite nanosphere's elastic modulus and shell thickness. The mechanical properties of the composite nanospheres were reasonably explained on the basis of the growth mechanism of PS/SiO composite nanospheres, in particular the SiO shell's formation process. Available research data of PS/SiO composite nanospheres in this work can provide valuable guidance for their effective application in surface engineering, micro/nanomanufacturing, lubrication, and so on.