For the first time, cefadroxil was synthesized from 7‐Amino‐3‐desacetoxycephalosporanic acid and d‐hydroxyphenylglycine methyl ester in [Bmim][NTf2]‐phosphate cosolvent capable of dissolving the substrates using the penicillin G acylase (PGA) immobilized on the micrometer‐size magnetic polymer microspheres having high activity of 2,083 U/g. The high synthesis/hydrolysis (S/H) ratio of 1.12 was achieved with 79.0% yield, where only the S/H ratio of 0.19 and yield of 20.0% was obtained using free PGA under the identical optimum reaction conditions. Cefadroxil had been synthesized efficiently in [Bmim][NTf2]‐phosphate cosolvent by the magnetic immobilized PGA, which illuminated that there are two very critical and essential designs, that is, effective support and suitable solvent system by PGA, in enzymatic synthesis of cefadroxil. Obviously, there is great potential for the magnetic immobilized PGA and ionic liquid solvent in application to biocatalysis.