The increasing popularity of lithium-ion battery systems, particularly in electric vehicles and energy storage systems, has gained broad research interest regarding performance optimization, thermal stability, and fire safety. To enhance the battery thermal management system, a comprehensive investigation of the thermal behaviour and heat exchange process of battery systems is paramount. In this paper, a three-dimensional electro-thermal model coupled with fluid dynamics module was developed to comprehensively analyze the temperature distribution of battery packs and the heat carried away. The computational fluid dynamics (CFD) simulation results of the lumped battery model were validated and verified by considering natural ventilation speed and ambient temperature. In the artificial neural networks (ANN) model, the multilayer perceptron was applied to train the numerical outputs and optimal design of the battery setup, achieving a 1.9% decrease in maximum temperature and a 4.5% drop in temperature difference. The simulation results provide a practical compromise in optimizing the battery configuration and cooling efficiency, balancing the layout of the battery system, and safety performance. The present modelling framework demonstrates an innovative approach to utilizing high-fidelity electro-thermal/CFD numerical inputs for ANN optimization, potentially enhancing the state-of-art thermal management and reducing the risks of thermal runaway and fire outbreaks.