The invention discloses an inorganic montmorillonoid composite cross-linked polymer microsphere, which comprises the following components in parts by weight: 0.1 to 10 parts of compound monomer, 10 to 50 parts of crylic acid monomer, 5 to 65 parts of acrylamide, 0.01 to 1 part of crosslink agent and 0.01 to 0.4 part of initiator; the initiator is a mixture of water-soluble initiator and oily initiator, and the compound monomer is the compound monomer of inorganic montmorillonoind and dimethyl diallyl ammonium chloride. The invention also provides a preparation method of the cross-linked polymer microsphere and an application of the prepared cross-linked polymer microsphere which is used as a profile control agent for sealing a high-permeability belt and a large pore in an oil reservoir in the oil field exploitation.