Lithium-ion batteries’ performance, degradation, and safety are highly sensitive to their operating temperature [1-3]. Depending upon the form-factor, construction, and thermal boundary conditions, large temperature variations may be present within a battery in more than one direction. Physics-based battery models, such as single-particle model (SPM), enhanced single-particle model (ESPM), tank-in-series model, and the widely used pseudo-two-dimensional (p2D) model, ignore the effect of temperature variations in one or more directions [4]. Specifically, p2D model can resolve temperature variation within anode, cathode, and separator of a single stack but this is often not useful as the temperature variation within a single stack will be negligible due to the small length scale. Also, a commercial-scale Li-ion battery is a multi-stack system with possibly significant temperature variation across the stacks as compared to within a single stack. The recently developed thermal tank-in-series battery model accounts for temperature variation across a multi-stack battery system but does not account for temperature variation in the direction parallel to the current collector [5]. In the case of large-format batteries, significant temperature variations are also expected along the directions corresponding to the longer dimensions. This would typically involve temperature variations in the directions parallel to the current collector. Multi-scale multi-domain (MSMD) models have been developed in the past to extend the single-stack level physics-based models to account for temperature nonuniformity in these directions [6-8]. However, temperature variation in the direction corresponding to the shortest dimension may also be appreciable due to the anisotropic/orthotropic nature of heat transfer in the battery system at the macroscale [9,10]. This is because the heat transfer in this direction may be severely impeded by the multi-stack construct leading to poor thermal conductivity in that direction. This in turn may lead to a large temperature gradient even along the direction corresponding to the shortest dimension of the large-format battery system. This suggests the need for careful formulation of MSMD battery models considering the construction, design parameters, and external thermal conditions of a particular battery system. In the present work, we propose a general three-dimensional modeling framework that accounts for the effect of the three-dimensional temperature field on the local variations in thermodynamics, transport processes, and reaction kinetics in the battery system. This type of battery modeling framework can be used to study nonuniform temperature distribution driven spatially uneven degradation, particularly in large-format batteries. Additionally, this modeling framework can help design physics-aware battery-specific thermal management systems to improve performance and reduce degradation. This will be a drastic departure from the present approach of designing battery thermal management system which treats the battery in a rather simplistic manner.