According to the theory of molecular design, crumb rubber was grafting activated with acrylamide and then used as asphalt binder modifier. An orthogonal three-factor, three-level test was designed to optimize the preparation process of modified asphalt. Softening point, viscosity, rutting factor, ductility, stiffness modulus and creep speed index were selected as evaluation indicators to study the effects of rubber content, shear time and shear temperature by variance analysis and range analysis. The results show that the rubber content had a significant impact on the performance of modified asphalt with grafting-activated crumb rubber, while the shear temperature and shear time had little effect. The grafting activated crumb rubber content of 20%, shear temperature of 170–190 °C, and shear time of 90 min was determined as the reasonable preparation process. Modified asphalt with common crumb rubber (CRMA) and modified asphalt with grafting activated crumb rubber (A-G-R) were prepared, respectively, using the reasonable process to analyze the influence of grafting activation of crumb rubber. The results indicate that A-G-R had smaller softening point difference, lower segregation index and more stable and uniform dispersed phase.