Abstract Large-scale computational models of the brain are necessary to accurately represent anatomical and functional variability in neuronal biophysics across brain regions and also to capture and study local and global interactions between neuronal populations on a behaviorally-relevant temporal scale. We present the methodology behind and an initial implementation of a novel open-source computational framework for construction, simulation, and analysis of models consisting of millions of neurons on high-performance computing systems, based on the NEURON and CoreNEURON simulators (Carnevale and Hines, 2006, Kumbhar et al., 2019). This framework uses the HDF5 data format and software library (HDF Group, 2021) and includes a data format for storing morphological, synaptic, and connectivity information of large neuronal network models, and an accompanying open-source software library that provides efficient, scalable parallel storage and MPI-based data movement capabilities. We outline our approaches for constructing detailed large-scale biophysical models with topographical connectivity and input stimuli, and present simulation results obtained with a full-scale model of the dentate gyrus constructed with our framework. The model generates sparse and spatially selective population activity that fits well with in-vivo experimental data. Moreover, our approach is fully general and can be applied to modeling other regions of the hippocampal formation in order to rapidly evaluate specific hypotheses about large-scale neural architectural features.