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Metal additive manufacturing (AM) provides an unprecedented opportunity to explore extreme microstructural regimes and their associated effects on the mechanical response of polycrystals. In this work, a single alloy (composition) belonging to the high-Mn steels family was processed by a conventional thermo-mechanical treatment and two different AM processes. This resulted in three different materials with strikingly diverse microstructures with respect to the microstructural size and polarity. The influence of disparities in the statistical microstructural features arising from the different processing conditions on the (macroscopic) mechanical response was investigated through an experiment-simulation approach. The (as-processed/as-built) microstructures were analyzed on the meso-scale for derivation of a set of parameters, namely meso-structure descriptors, which adequately describe the meso-structural heterogeneity features. To link the microstructure and mechanical properties, we used a physics-based crystal plasticity modeling approach in the framework of full-field polycrystal homogenization. The meso-structure descriptors together with the submeso-scale/constitutive microstructural parameters were used to simulate the (anisotropic) mechanical response of the aforementioned materials. Then, for a reduced-order quantitative assessment of the effect of microstructural polarity on the anisotropic mechanical response, the plastic anisotropy indices were defined and calculated using the simulation results. This study provides new insights into the primary microstructural effects (the size and polarity effects) on the mechanical (stress and strain hardening) response of polycrystals as well as the propensity of micro-mechanisms accommodating polycrystal plasticity in highly different microstructural regimes, particularly those typically obtained by metal AM.