Thermal stabilities of L1₂-Al₃Sc nano-precipitates are critical for the thermotolerance of Al-Sc based alloys. Previous experiments have suggested that different alloying elements may have different segregation behaviors at the L1₂-Al₃Sc/Al interface, which can exert different influences on the thermal stability of L1₂-Al₃Sc nano-precipitates. To clarify the responsible mechanism from a quantitative approach, first-principles calculations of energetics are performed in this work, to investigate the segregation behaviors of transition-metal elements Cu and Ti at the L1₂-Al₃Sc/Al interface. The results suggest that both Cu and Ti can segregate to the interface, and substitute Al or Sc sites on its Al side with different thermodynamic driving forces. Given a temperature, segregation amount is largely determined by the initial elemental concentration in the Al matrix. The higher the segregation driving force and the initial matrix concentration are, the higher the equilibrium segregation amount (or the maximum interfacial coverage) could be. With an initial matrix atomic concentration of 1%, the maximum interfacial coverage of Ti can reach up to 80% (0.8 monolayer layer (ML)) while that of Cu is less than 4% (0.04 ML) at T = 600 K.