The self-assembly of palladium-based cages is frequently rationalized via the cumulative enthalpy (ΔH) of bonds between coordination nodes (M, i.e., Pd) and ligand (L) components. This focus on enthalpic rationale limits the complete understanding of the Gibbs free energy (ΔG) for self-assembly, as entropic (ΔS) contributions are overlooked. Here, we present a study of the M2linL3 intermediate species (M = dinitrato(N,N,N′,N′-tetramethylethylenediamine)palladium(ii), linL = 4,4′-bipyridine), formed during the synthesis of triangle-shaped (M3linL3) and square-shaped (M4linL4) coordination macrocycles. Thermochemical analyses by variable temperature (VT) 1H-NMR revealed that the M2linL3 intermediate exhibited an unfavorable (relative) ΔS compared to M3linL3 (triangle, ΔTΔS = +5.22 kcal mol−1) or M4linL4 (square, ΔTΔS = +2.37 kcal mol−1) macrocycles. Further analysis of these constructs with molecular dynamics (MD) identified that the self-assembly process is driven by ΔG losses facilitated by increases in solvation entropy (ΔSsolv, i.e., depletion of solvent accessible surface area) that drives the self-assembly from “open” intermediates toward “closed” macrocyclic products. Expansion of our computational approach to the analysis of self-assembly in PdnbenL2n cages (benL = 4,4'-(5-ethoxy-1,3-phenylene)dipyridine), demonstrated that ΔSsolv contributions drive the self-assembly of both thermodynamic cage products (i.e., Pd12benL24) and kinetically-trapped intermediates (i.e., Pd8cL16).