The invention relates to the technical field of chemical synthesis, in particular to a preparation method of polysubstituted isoindoline. The preparation method includes following steps: in the presence of a catalyst, lewis acid and a zinc reagent, allowing ketone shown as a formula II to react with imine shown as a formula III through C-H activation/C-N to obtain polysubstituted isoindoline shown as a formula I, wherein in the formulas I, II and III, R1 refers to monosubstituted group or polysubstituted group on benzene ring and is one or multiple of hydrogen, substituted or unsubstituted alkyl with 1-10 carbon atoms, substituted or unsubstituted alkoxy with 1-10 carbon atoms, aryl, halogen or aromatic ring obtained by condensing with the benzene ring, R2 is chosen from hydrogen or alkyl with 1-10 carbon atoms, R3 is one of aryl, heteroaryl or aromatic ring obtained by condensing with the benzene ring, and R4 is chosen from aryl or heteroaryl sulfonyl. Synthesis of polysubstituted isoindoline is realized by utilizing reaction of ketone and imine in the solvent in the presence of the catalyst, the lewis acid and the zinc reagent.