The invention discloses a neoprene adhesive subjected to secondary graft modification and a preparation method of the neoprene adhesive. The neoprene adhesive comprises the following raw materials (in percentage by weight): 10%-15% of neoprene, 6.3%-13% of grafted monomers, 0.1%-0.5% of initiating agents, 5%-10% of acetone, 15%-30% of butanone, 10%-20% of ethyl acetate, 10%-20% of dimethyl carbonate, 8%-20% of methyl cyclohexane, 5%-10% of thickening agents and 0.3%-1% of terminating agents. The preparation method comprises the following steps of sequentially adding acetone, butanone, ethyl acetate, dimethyl carbonate and methyl cyclohexane, and uniformly mixing and stirring; adding neoprene, and stirring for 2-4 hours; adding a part of the initiating agents, further stirring, then dropping first grafted monomers to react for 0.5-1 hour, and adding second grafted monomers and the rest of initiating agents; adding a terminating agent, and then adding tackifying resin; regulating viscosity, and then discharging. The neoprene adhesive disclosed by the invention is subjected to the secondary graft modification through multiple monomers. The product has the characteristics of high comprehensive property and good environmental friendliness and is suitable for industries, such as furniture making, shoe making and luggage.