Multi‐yolk@shell mesoporous silica spheres are becoming more and more attractive as high‐performance catalysts because of their high surface areas, variable pore sizes, and low densities. In this work, a NiCuFe2O4 magnetic core with a shell of mesoporous silica mesoporous has been prepared in an easy two‐step procedure. The prepared multi‐yolk@shell NiCuFe2O4@mSiO2 spheres were characterized by using FT‐IR, XRD, VSM, EDX, BET, FE‐SEM and HR‐TEM techniques. These unique multi‐yolk@shell NiCuFe2O4@mSiO2 spheres demonstrated high catalytic activity for the synthesis of pyrimidoquinolines. Also, this method exposes obvious benefits such as catalyst recyclability, easy reaction condition, simplicity of work up, high product yields and short reaction times.