Low salinity effect has been in the center of attention as a cost-effective and environmentally friendly technique. Wettability alteration of the oil/brine/mica system appears to be the identified mechanism(s) to trigger the low salinity effect. While the effect of water chemistry and minerology on the wettability of the system has been extensively investigated, few studies have investigated the effect of specific function groups from crude oil on the system wettability, limiting the understanding of how specific functional group contributes to the wettability. We thus experimentally measured the adhesion forces between mica surfaces and functional groups (e.g., C6H5–, CH3–, COOH–, and NH2–) in the presence of different aqueous ionic solutions using chemical force microscopy (CFM). Moreover, to understand the contribution of the structural force, the traditional Derjaguin–Landau–Verwey–Overbeek (DLVO) theory was extended (denoted as EDLVO) to fit the force profiles using a Gauss model. Our results showed that the adhesion force between mica and functional groups in a decreasing order was –NH2 > –COOH > –CH3 > –C6H5. We also found that while DLVO forces strongly affected the tip-surface contact due to the interactions among oil/brine/mica interfaces, the structural forces also played an important role in a distance of 1–20 nm due to the presence of H-bonds between COOH-terminated or NH2-terminated tip and mica surface. We therefore conclude that the structural force largely contributes to the adhesion force due to the hydrophilicity or polarity of functional groups, and nucleophilic property (such as phenyl group). Our results suggest that the polarity of the crude oil needs to be considered to screen a candidate reservoir for low salinity water flooding projects.