Human serum albumin (HSA) is the most abundant blood protein and is responsible for the transport of many exogenous compounds, including clinically deployed and investigational drugs: most are organic. Here, Ni(II), Pd(II) and Pt(II) chelates of a tetradentate bis(pyrrole-imine) ligand, H2PrPyrr, were used to delineate how the identity of the d8 metal ion impacts the compound’s affinity for HSA. Fluorescence quenching data acquired on the native protein and HSA bound to site-specific probes showed the compounds target sites close enough to its single Trp-214 residue (subdomain IIA) to quench the fluorophore. The bimolecular quenching rate constants, k_q, were of the order of 10^1 to 10^4 times higher than the maximum diffusion-controlled collision constant of a biomolecule in water (10^10 M-1 s-1), reflecting a static fluorescence quenching mechanism. The Stern-Volmer constants, K_SV, spanned the range 10^4 M-1 to 10^6 M-1 at 37 oC, while the affinity constants, K_a, ranged from ~3 x 10^3 M-1 to ~8 x 10^7 M–1 at 37 oC, and followed the order Pd(PrPyrr) >> Pt(PrPyrr) > Ni(PrPyrr) > H2PrPyrr. The thermodynamics reflect enthalpically driven ligand uptake, hinging mainly on London dispersion forces (metal ion dependent), along with general multi-site binding. Notably, two reactive species exist for the Pd(II) system, affording the complex HSA•{Pda}{Pdb}. Molecular docking simulations (GLIDE XP) support the spectroscopic data, confirming that all ligands can target multiple binding sites in silico—all within ~20 Å of Trp-214. Although far- and near-UV CD spectroscopy indicated that the optically inactive ligands negligibly perturb the secondary and tertiary structure of HSA, substantial induced CD (ICD) spectra were recorded for the protein-bound ligands and could be simulated by hybrid QM:MM TD-DFT methods. This study highlights how appropriately chelated square planar d8 metal ions neither decompose nor demetallate after uptake by HSA, proving that metallodrug transport and delivery by HSA might be more feasible than generally acknowledged.