The functionalization of CO2 mediated by a series of U(IV) mixed-sandwich compounds, (COTTIPS2)Cp*UR (R = -CH3, -CH2Ph, -CH2TMS, -CH(TMS)(2), -NHPh, -OPh, -SPh, -SePh; COTTIPS2 = C8H6((SiPr3)-Pr-i-1,4)(2); Cp* = C5Me5; TMS = SiMe3), was investigated by the density functional theory method. A two-step mechanism was revealed, in which the insertion of CO2 into the U-C bond was identified as the rate-determining step via a transition state featured by a four-membered ring with a free-energy barrier of 18.8 kcal/mol to the reaction of the (COTTIPS2)Cp*UCH3 system. The whole reaction was strongly exothermic by 45.0 kcal/mol. Substitution effect was discussed, including the bulkiness of the R group and the nature of the ligating atom, and steric hindrance and electrostatic interactions were found to be responsible for the observed variation in reactivity. The reactivity of U(III) and U(IV) complexes in CO2 functionalization was also compared and discussed. The results were consistent with experimental studies and complemented with molecular level of understanding on the mechanisms of CO2 functionalization promoted by tetravalent U complexes.