• Presents a novel computationally-efficient reconstruction of 3D RVE model of second-phase particle-strengthened AA7075-O sheet with real distribution of particles based on FIB-SEM techniques. • Three types of second-phase particles (i.e., irregularly-shaped iron-rich particle Al 3 Fe, elliptically-shaped particle MgZn 2 , and needle-like particle CuAl 2) are determined using SEM-based EDS and EBSD techniques. • Presents a systematic study of the overall elastic-plastic response by developing and applying a hybrid experimental analysis and computational modeling framework. • Good agreement is observed in the comparison of RVE results with that of in-situ SEM tensile tests, indicating that the real 3D microstructure-based RVE models can accurately predict the plastic deformation and interfacial failure evolution in AA7075-O sheet. This paper addresses the challenge of reconstructing randomly distributed second-phase particle-strengthened microstructure of AA7075-O aluminum sheet material for computational analysis. The particle characteristics in 3D space were obtained from focused ion beam and scanning electron microscopy (FIB-SEM) and SEM-based Electron Backscatter Diffraction/Energy Dispersive X-ray Spectrometry (EBSD/EDS) techniques. A theoretical framework for analysis of elastic-plastic deformation of such 3D microstructures is developed. Slip-induced shear band formation, void initiation, growth and linkage at large plastic strains during uniaxial tensile loading were investigated based on reconstructed 3D representative volume element (RVE) models with real-distribution of particles and the results compared with experimental observations. In-situ SEM interrupted tension tests along transverse direction (TD) and rolling direction (RD), employing microscopic-digital image correlation (μ-DIC) technique, were carried out to investigate slip bands, micro-voids formation and obtain microstructural strain maps. The resulting local strain maps were analyzed in relation to the experimentally observed plastic flow localization, failure modes and local stress maps from simulations of RVE models. The influences of particle size, shape, orientation, volume fraction as well as matrix-particle interface properties on local plastic deformation, global stress-strain/strain-hardening curves and interfacial failure mechanisms were studied based on 3D RVE models. When possible, the model results were compared with in-situ tensile test data. In general, good agreement was observed, indicating that the real 3D microstructure-based RVE models can accurately predict the plastic deformation and interfacial failure evolution in AA7075-O aluminum sheet. [ABSTRACT FROM AUTHOR]