The association processes between engineered TiO2 nanoparticles and Suwannee River humic acids are investigated by isothermal titration calorimetry and by measuring the exchanged heat during the binding process, allowing the determination of thermodynamic (change in enthalpy, Gibbs free energy and entropy) and reaction (binding affinity constant, reaction stoichiometry) parameters. Our results indicate that strong TiO2–Suwannee River humic acid interactions are entropically and enthalpically favorable with exothermic binding reactions and that the mixing order is also an important parameter. High humic acid concentrations induce homoagglomeration (“self”-assembly) and are shown to favor an enthalpically driven association process. Light scattering techniques are also considered to investigate the influence of TiO2 surface charge modifications and agglomeration mechanisms. Patch and bridging mechanisms are found to result in the formation of large agglomerates once charge inversion of TiO2–humic acid complexes is achieved. Moreover, van der Waals interactions are also found to play a significant role during interaction processes due to the amphiphilic character of humic acids.