Elevated levels of protein expression and aberrant metal exposure have been reported in many neurodegenerative diseases, including Huntington’s Disease (HD). While there is currently no cure for HD, metal chelation therapies have been shown to assuage disease symptoms including chorea. These observations underscore the critical need to understand how metal-protein interactions are involved in disease pathogenesis. Our objective in this work is to elucidate the role of copper (Cu) and other biorelevant metals in HD and, more specifically, their interactions with the huntingtin protein (htt). We aimed to characterize the Cu-htt interaction and speciation trends in our in vitro HD system, as well as the influence of disease-relevant Cu concentrations on protein oligomerization/aggregation both in vitro and in vivo. We utilized multiple spectroscopic techniques (circular dichroism, electron paramagnetic resonance, UV-Vis absorption, dynamic light scattering, and mass spectrometry) that cover a broad range of energy scales, allowing us to characterize protein structure at the molecular, secondary structure, and quaternary structure levels. Additionally, site-directed mutagenesis of several putative metal binding residues was used to define the roles of specific amino acids in mediating oligomerization/aggregation, metal binding, and redox chemistry. Taken together, our work has led to the first report of multiple copper binding sites in non-pathological htt and provides insight into one pathway for depletion of native htt pools that may contribute to HD.