Isothermal titration calorimetry (ITC) is a technique that allows us to accurately determine the thermodynamic parameters that characterize a binding interaction between two molecular systems. However, this technique has not had a wide application in petroleum science. This study is an attempt to determine the adhesion of different fluids onto a rock surface through ITC experiments. Two artificial brines with different ionic composition were titrated into chalk powder, and then crude oil was added to those systems in order to mimic the processes that take place in an oil reservoir. In addition, the wettability alteration process associated with smart water flooding was investigated from a thermodynamic point of view. The results from the ITC experiments suggest that the interaction between smart water and chalk + brine + oil systems is both exothermic and endothermic. The exothermic heat response indicates chemisorption of sulfate (SO42–) onto the mineral lattice, whereas the endothermic response proved the substitution of carboxylate complexes from the chalk surface by magnesium (Mg2+). The ITC results also show that the performance of diluted seawater seems to be higher than smart water with increased sulfate concentration. This is due to dynamic processes like brine dilution resulting in an increased osmotic pressure.