This study aims at understanding effects of sub-core scale petrophysical heterogeneity on CO2-brine multiphase flow properties during CO2 injection in samples of the Minnelusa Formation in Wyoming, representing differing lithofacies. Unsteady-state CO2-brine drainage tests were performed on a core sample from a dune deposit with laminated bedding and poorly sorted grain distribution. To highlight the role of low-porosity and low-permeability bedding layers (LLBL) on CO2 migration during CO2 injection, a contrasting coreflooding experiment was conducted on a sample of well-sorted sandstone collected from an interdune deposit. Assisted history matching was used to estimate the corresponding core-scale relative permeability curves, a procedure that reveals heterogeneity-dependent behavior. The simulated brine production from the optimal history matching case suggests that the main variation in multiphase flow properties could be attributed to internal permeability structures, i.e. sub-core scale LLBL, leading, in turn, to capillary pressure heterogeneity. CO2 sweep efficiency and distribution in heterogeneous Eolian sandstone are hard to estimate based solely on the limited number of coreflooding experiments, due to LLBL properties variability. Consequently, sensitivity analyses for the properties of sub-core scale LLBL on core-scale brine production were conducted using the developed model. Analyses indicate that the residual brine saturation and thickness of LLBL have a more significant effect on bulk brine production, whereas the impact of CO2 end-point relative permeability of LLBL on bulk brine production is negligible. In addition, comparison results show that ignoring the sub-core scale heterogeneity (e.g. sub-core scale relative permeability) during CO2 injection can create significant uncertainties in storage and fluid flow displacement in simulated results, due to important flow effects and thereby physically insightful responses. Overall, this study provides us with a deeper understanding of core-scale CO2-brine multiphase flow properties for CO2 geological storage in heterogeneous sandstones and gained us insights into CO2-brine multiphase flow upscaling in heterogeneous geological models. Our approach needs to be incorporated in upscaling procedures to avoid smearing key small-scale features, relevant to multiphase flow behaviour.