Scandium (Sc) is crucial for refining the grain size and enhancing strength and toughness of aluminum (Al) alloys. In this work, 2195-xSc Al–Li alloys were systematically designed and fabricated through the integration of inert gas protection and ultrasonic treatment. The effect of Sc on the grain refinement of the 2195 Al–Li alloy, the enhancement of its mechanical properties, and the structural evolution of the Al3Sc primary phase was thoroughly investigated. Experimental results demonstrate that the incorporation of Sc leads to a gradual transition in the grain structure of 2195 Al–Li alloys from columnar grains to equiaxed grains and the grain size diminishes from 231 μm to 42 μm, achieving a maximum grain refinement rate of 81.8 %. When the Sc concentration surpasses 0.6 wt%, the grain refinement efficiency plateaus. The co-precipitation of primary Al3Sc and L12-structured Al3(Sc, Zr) dispersoids synergistically induces a pronounced Zener pinning effect on grain boundaries (GBs). It has been established that the Al3(Sc, Zr) exhibits a core-shell structure (CSS), characterized by a Sc-rich core enveloped by a Zr-rich region. Concurrently, the mechanical properties at both the top (HP) and bottom (BP) positions of the ingot demonstrate significant enhancement. At the top position, the tensile strength (TS) and elongation (El) rose from 134 MPa to 0.21 % to 221 MPa and 2.42 %, reflecting relative increases of 64.9 % and 1052.4 %, respectively. This research presents a detailed investigation into the structure and formation mechanisms of the Al3Sc phase, as well as the underlying mechanisms of grain refinement and toughness enhancement in 2195-xSc Al–Li alloys.