Minerals are the chief constituents of rocks and have varied properties, such as the surface area, surface charge, site density, etc. Hence, numerous interactions are bound to occur in a reservoir during rock–fluid (i.e., rock, crude oil and brine) interactions. This study seeks to assess the role of the mineralogical composition in the wettability of sandstone rocks (SRs) and mineral mixture (MM) using both surface complexation modeling (SCM) and a flotation test. From the considered sandstone rocks, both the experimental results and the simulated counterparts revealed that the SRs were preferentially hydrophilic. For the MM, when the mass fraction of the hydrophobic mineral was increased, the affinity of the MM became slightly hydrophobic, and vice versa. For the dominant sandstone reservoir rock minerals with predominantly negatively charged surfaces, negligible oil adsorption took place due to the interfacial repulsive forces at the oil–brine and mineral–brine interfaces. For the MM with low calcite content, the wetting preference was influenced by the mineral with a prominent surface area. Our developed model portrayed that the main mechanism of oil adhesion onto sandstone minerals was divalent cation bridging. Nonetheless, adhesion of carboxylate (>COO−) onto the illite, montmorillonite and calcite sites also took place, with the latter being more pronounced.