The sedimentation problem of waste rubber powder in asphalt not only restricts the engineering application of rubber powder asphalt, but also impedes the recycling of waste rubber. To solve this industry malady, this study designs and prepares three different chemical structures of rubber powder, and systematically investigates the influence of the chemical structure of rubber powder on the compatibility of rubber powder asphalt by cigar tube test, dynamic shear rheology test, microscopic characterization analysis, and molecular dynamics method. The microstructure results indicate that new characteristic peaks (such assulfonic acid groups, thiol groups, and amino groups) appeared in the infrared spectra of each of the modified rubber powder. The elemental analysis further proves that the sulfur and hydrogen contents of the mechanochemical modified rubber powder (AR) have been reduced, the carbon and hydrogen contents of the sulfonated modified rubber powder (SR) have been reduced, and the nitrogen contents of the tetraethylenepentamine with mechanochemical co-modified rubber powder (NR) have been increased. These facts indicate that different chemically structured rubber powder have been successfully prepared. The macroscopic results show that NR and asphalt blends has a lower softening point difference (2.1 ℃) and segregation index (12%), followed by SR and AR, and waste rubber powder (WR) and asphalt blends is the highest in softening point difference (6.3 ℃) and segregation index (35%). Microscopic characterization results show that NR, SR, and AR can form a fuzzy phase interface with asphalt, and further quantitative analysis finds that NR has the highest compatibility index with asphalt (80%), followed by SR and AR, and WR has the lowest compatibility index with asphalt (36%). Molecular dynamics simulation indicates that the solubility parameter of NR and asphalt is the closest and its difference is the smallest (0.4 (J/cm3) 1/2) as well as the strongest intermolecular interactions (-563.93 kJ/mol), followed by SR, AR, and WR. All the above results reveal that the order of compatibility between four types of chemical structure rubber powder and asphalt is NR > SR > AR > WR. Furthermore, based on macroscopic, microscopic, and molecular dynamics simulation, the compatibility mechanism of different chemically structured rubber powder with asphalt could be that the acidic groups in SR and the thiol functional groups in AR can be dissolved with the acidic groups in asphalt based on the principle of similar solubility, which improves the compatibility of the rubber powder with asphalt. The NR contains strong polar alkaline groups, which can be combined with the acidic components of asphalt based on the principle of acid-base neutralization reaction, thereby improving the compatibility of the rubber powder with asphalt. In view of the above, it is not difficult to see that the combination of tetraethylenepentamine and mechanochemically co-modified rubber powder and asphalt has a promising application in the future construction of pavement engineering and recycling of waste tire resource.