As one of the most important fuel candidates in fast reactor, MOX fuel is critical in the advanced fuel cycle. Thermal conductivity of MOX fuel is a key parameter in its service life, which will affect the safety of fast reactor. The empirical formula of themal conductivity variation was usually obstained by fitting the experimental data. However, few investigations have been conducted on a theoretical basis to analyze the thermal conductivity of MOX fuel with different Pu content and oxygen-to-metal ratio (O/M). In this paper, the effect of various point defects on the thermal conductivity of MOX fuel was investigated by analyzing the influence factors of thermal conductivity for MOX samples with different Pu content and O/M in light of the classical phonon conduction theory. The results show that the phonon conduction models can be used to predict the thermal conductivity of MOX fuels with different compositions. The oxygen vacancies induced by lower O/M in MOX fuel predominate in deterimining the thermal conductivity, rather than the substituted ions point defects with small mass and radius difference. This work is beneficial to the prediction of thermal conductivity and material design of MOX fuels with different compositions.