Five simulation models of chloroprene rubber (CR)/polyurethane (PU) with different composition ratios (9/1, 8/2, 7/3, 6/4, 5/5) are constructed and simulated using molecular dynamics (MD) simulation. The effects of PU content on blend compatibility and mechanical properties are investigated using solubility parameters, the Flory–Huggins interaction parameter, binding energy, glass transition temperature, and the radial distribution function. The objectives of this study are to develop a computational model based on MD techniques to investigate the compatibility and mechanical properties of CR/PU blends. The results of the solubility parameter indicated that PU has good miscibility with CR. The analysis of interaction parameters, binding energy, glass transition temperature, and radial distribution function show that CR/PU blends with mass ratios of 9/1, 8/2, and 7/3 have good compatibility. Moreover, the analyses of binding energy, pair correlation function, and radial distribution function reveal the reasons for the variation in mechanical properties of the blend systems. Additionally, the correctness of the calculation model and the results are verified by experimental tests and analyses.