It is a practically significant issue to refine and modify industrial Al-Si casting alloy to improve its properties. In the present study, a novel refiner Al-3Ti-4.35La alloy, prepared by a melt-reaction method, was used, combined with Sr to refine the as-cast A356 alloy. Their effects on the as-cast microstructures and mechanical properties of A356 alloy were investigated. The results indicate that the combined addition of Al-3Ti-4.35La intermediate alloy and Sr can improve the microstructure and enhance the mechanical properties of A356 alloy. After adding 0.3wt.% Al-3Ti-4.35La and 0.03wt.% Sr to the as-cast A356 alloy, the average grain size of α-Al decreases from 693.47 µm to 264.13 µm (a decrease of 61.91%), the secondary dendrite arm spacing (SDAS) is decreased by 47.8% from 32.09 µm to 16.75 µm, and the eutectic Si is transformed from an acicular structure to short rods and a granular structure. The ultimate tensile strength (UTS) and elongation (EL) of the as-cast A356 alloy modified by Al-3Ti-4.35La and Sr reach 216.3 MPa and 10.6%, which are enhanced by 29.54% and 134.66% compared with the unmodified alloy, respectively. The fracture mode is transformed from transgranular fracture to intergranular fracture, and the ductile toughness of the alloy is improved. After adding the Al-3Ti-4.35La and Sr, the undercooling for the nucleation of α-Al and eutectic Si increases, leading to an accelerated nucleation rate and an increased number of nuclei, which shortens the duration of the eutectic reaction and consequently inhibits grain growth.