The selective extraction of minor actinides(III) from the lanthanides(III) is a key step for spent fuel reprocessing. Theoretical calculations of geometries, electronic structures, coordination complexion, and thermodynamic properties of the actinides are essential for understanding the separation mechanisms and relevant reactions. This article presents a critical review of theoretical studies on actinide systems involved in the An(III)/Ln(III) separation process. We summarize various theoretical methods for electronic and molecular scale modeling and simulations of actinide coordination systems. The complexing mechanisms between metal cations and organic ligands and the strategies for the design of novel ligands for separation are discussed as well.Highlights► We review recent advances in computational modeling and simulations on the An(III)/Ln(III) separation process. ► Various theoretical methods for electronic and molecular-scale modeling and simulations of actinide systems are summarized. ► The complexation between soft-donating ligands and An(III)/Ln(III) ions are explored. ► The strategies for design of novel organic ligands for separation are discussed.