Anterior lumbar plate (ALP) systems have been widely used as an effective interbody fusion device for treating spinal cord compression. However, clinical complications, such as implant loosening and breakage, still occur. Past studies have investigated the effects of the screw orientation on the interfacial strength, but these studies were inconsistent. The purpose of this study was to identify an ALP system with excellent interfacial strength by varying the screw orientation. Three-dimensional finite element models of L4–L5 segments with an ALP system were first constructed. A neurogenetic algorithm, which combines artificial neural networks and genetic algorithms, was subsequently developed to discover the optimum plate design. Finally, biomechanical tests were conducted to validate the results of the finite element models and the engineering algorithm. The results indicated that the interfacial strength of the optimum plate design obtained using the neurogenetic algorithm was excellent compared with the other designs and that all of the locking screws should be inserted divergently. Both the numerical and experimental outcomes can provide clinical suggestions to surgeons and help them to understand the interfacial strength of ALP systems in terms of the screw orientation.