In Al–Cu–Li–Mg alloys, Li not only imposes the effects on the precipitation of T1, δ′, θ′, S et al., but also segregates to the S (Al2CuMg)/Al interface to stabilize the S precipitates. However, such segregation behavior could not be characterized experimentally at the atomic degree due to the low mass of Li. Also, the fine structure of S/Al interface is not yet clear. This work applied first-principles calculations to study these issues. The numerical values of surface energies for three non-stoichiometric surfaces (Al-1, Al-2, and CuMg terminations) of Al2CuMg (001) surface were calculated as ~ 1.3 J/m2 using a special method. The lowest energy of Al2CuMg (001)/Al (021) structure was obtained based on the calculation of energies and interface separated work. The segregation of Li at Al2CuMg (001)/Al (021) interface was clarified: (i) Li substituted not only one Al atom, but also all the Al atoms of the ‘3’ layer rather than the ‘1’or ‘2’ layer of the Al matrix side at the interface, (ii) Li that substituted Al atoms of the Al matrix side preferred to play on the role of Mg in Al2CuMg, trying to expand Al2CuMg bulk to maintain the interface stability, (iii) Li segregation is helpful to improve interface strength. This work provides a considerable insight for Li segregation to Al2CuMg (001)/Al (021) interface in Al–Cu–Li–Mg alloys.