The article presents a mathematical model for calculation of nonstationary hydraulic and separation processes in a gas centrifuge (GC) cascade for separation of multicomponent isotope mixtures. The model has been applied to calculate the parameters of nonstationary processes in a GC cascade for separation of krypton, germanium and tungsten isotopes. As a result, the specifics of the excess holdup distribution along the cascade stages has been identified, and variations of the isotope concentrations in a nonstationary process have been revealed. The data obtained show that the proposed mathematical model is able to adequately describe nonstationary hydraulic processes in GC cascades for separation of multicomponent isotope mixtures. Highlights: Mathematical model of cascade for separation of multicomponent isotope mixture has been developed. The model verification has been done. The isotope transient regularities into cascade during nonstationary processes has been identified.