BackgroundDiffuse optical tomography (DOT) provides three‐dimensional image reconstruction of chromophore perturbations within a turbid volume. Two leading strategies to optimize DOT image quality include, (i) arrays of regular, interlacing, high‐density (HD) grids of sources and detectors with closest spacing less than 15 mm, or (ii) source modulated light of order ∼100 MHz.PurposeHowever, the general principles for how these crucial design parameters of array density and modulation frequency may interact to provide an optimal system design have yet to be elucidated.MethodsHerein, we systematically evaluated how these design parameters effect image quality via multiple key metrics. Specifically, we simulated 32 system designs with realistic measurement noise and quantified localization error, spatial resolution, signal‐to‐noise, and localization depth of field for each of ∼85 000 point spread functions in each model.ResultsWe found that array density had a far stronger effect on image quality metrics than modulation frequency. Additionally, model fits for image quality metrics revealed that potential improvements diminish with regular arrays denser than 9 mm closest spacing. Further, for a given array density, 300 MHz source modulation provided the deepest reliable imaging compared to other frequencies.ConclusionsOur results indicate that both array density and modulation frequency affect the spatial sampling of tissue, which asymptotically saturates due to photon diffusivity within a turbid volume. In summary, our results provide comprehensive perspectives for optimizing future DOT system designs in applications from wearable functional brain imaging to breast tumor detection.