In this article, a novelvertical wire-bonding interconnect structure is intelligently modeled and optimized with general artificial neural network (GRNN) and genetic algorithm (GA) for multilayered system in package. A compensation structure is constructed with a hybrid inductive and capacitive technique, while a capacitive stripline with series inductive short-end via is designed underneath the 50-Ω transmission line. The GRNN algorithm is employed to build the electromagnetic model databases during the procedure of GA optimization. In comparison with the conventional optimization algorithm, the output performances can be directly achieved with collaboratively combined methods, which can significantly reduce the calculation time. From the measurement results, the return loss is improved significantly while the parasitic inductive behavior of the bonding wire is eliminated with the presented design. Moreover, compared with the traditional compensation techniques, no additional area is occupied on the surface plane of the wire-bonding interconnection, which is more suitable for the high-integrated circuit system.