The entropic and enthalpic driving forces for encapsulation versus sequential exterior guest binding to the [Ga4L6]12– supramolecular host in solution are very different, which significantly complicates the determination of these thermodynamic parameters. The simultaneous use of complementary techniques, such as NMR, UV–vis, and isothermal titration calorimetry, enables the disentanglement of such multiple host–guest interactions. Indeed, data collected by each technique measure different components of the host–guest equilibria and together provide a complete picture of the solution thermodynamics. Unfortunately, commercially available programs do not allow for global analysis of different physical observables. We thus resorted to a novel procedure for the simultaneous refinement of multiple parameters (ΔG°, ΔH°, and ΔS°) by treating different observables through a weighted nonlinear least-squares analysis of a constrained model. The refinement procedure is discussed for the multiple binding of the Et4N+ guest, but it is broadly applicable to the deconvolution of other intricate host–guest equilibria.