An efficient and accurate two-stage approach, based on the artificial neural network (ANN) and an enhanced particle swarm optimization (EPSO) approach for model updating of structures using incomplete measurements, is proposed in this study. The first stage, preliminary model updating, employs the ANN to quickly learn the mapping relationship between the natural frequencies and stiffness of the structure using a few training, validation, and testing instances. The inputs and outputs of the ANN are the natural frequencies and stiffness of the structure, respectively. The ANN’s training, validation, and testing instances are extracted through Latin hypercube sampling. The ANN-predicted stiffness provides an excellent basis for determining and reducing the search space of the optimal stiffness in the second stage. The second stage, detailed model updating, searches for the optimal stiffness of the structure by using the EPSO approach. The EPSO approach improves particle swarm optimization (PSO) by employing an elite crossover strategy to avoid trapping in the local optimum and premature convergence. The feasibility and effectiveness of the proposed two-stage approach for stiffness updating of shear building structures using incomplete measurements are demonstrated by numerical and experimental examples. The results present that the proposed two-stage approach improves the computational efficiency and solution quality of the GA (Genetic Algorithm) and PSO for stiffness updating of shear building structures.