Regional innovation performance is an important indicator for decision-making regarding the implementation of policies intended to support innovation. However, patterns in regional innovation structures are becoming increasingly diverse, complex and nonlinear. To address these issues, this study aims to develop a model based on a multi-output neural network. Both intra- and inter-regional determinants of innovation performance are empirically investigated using data from the 4th and 5th Community Innovation Surveys of NUTS 2 (Nomenclature of Territorial Units for Statistics) regions. The results suggest that specific innovation strategies must be developed based on the current state of input attributes in the region. Thus, it is possible to develop appropriate strategies and targeted interventions to improve regional innovation performance. We demonstrate that support of entrepreneurship is an effective instrument of innovation policy. We also provide empirical support that both business and government R&D activity have a sigmoidal effect, implying that the most effective R&D support should be directed to regions with below-average and average R&D activity. We further show that the multi-output neural network outperforms traditional statistical and machine learning regression models. In general, therefore, it seems that the proposed model can effectively reflect both the multiple-output nature of innovation performance and the interdependency of the output attributes. © 2017 Hajek, Henriques. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.