This paper presents a major step in the development and validation of a systematic prototype-based methodology for designing multilayer feedforward neural networks to model nonlinearities common in engineering mechanics. The applications of this work include (but are not limited to) system identification of nonlinear dynamic systems and neural-network-based damage detection. In this and previous studies (Pei, J. S., 2001, “Parametric and Nonparametric Identification of Nonlinear Systems,” Ph.D. thesis, Columbia University; Pei, J. S., and Smyth, A. W., 2006, “A New Approach to Design Multilayer Feedforward Neural Network Architecture in Modeling Nonlinear Restoring Forces. Part I: Formulation,” J. Eng. Mech., 132(12), pp. 1290–1300; Pei, J. S., and Smyth, A. W., 2006, “A New Approach to Design Multilayer Feedforward Neural Network Architecture in Modeling Nonlinear Restoring Forces. Part II: Applications,” J. Eng. Mech., 132(12), pp. 1301–1312; Pei, J. S., Wright, J. P., and Smyth, A. W., 2005, “Mapping Polynomial Fitting Into Feedforward Neural Networks for Modeling Nonlinear Dynamic Systems and Beyond,” Comput. Methods Appl. Mech. Eng., 194(42–44), pp. 4481–4505), the authors do not presume to provide a universal method to approximate any arbitrary function. Rather the focus is given to the development of a procedure which will consistently lead to successful approximations of nonlinear functions within the specified field. This is done by examining the dominant features of the function to be approximated and exploiting the strength of the sigmoidal basis function. As a result, a greater efficiency and understanding of both neural network architecture (e.g., the number of hidden nodes) as well as weight and bias values is achieved. Through the use of illuminating mathematical insights and a large number of training examples, this study demonstrates the simplicity, power, and versatility of the proposed prototype-based initialization methodology. A clear procedure for initializing neural networks to model various nonlinear functions commonly seen in engineering mechanics is provided. The proposed methodology is compared with the widely used Nguyen–Widrow initialization to demonstrate its robustness and efficiency in the specified applications. Future work is also identified.