Recovery of gangue pyrite and its accidental activation are vital issues in flotation of complex sulfide ores. This work was performed by cyclic voltammetry (CV) and flotation tests to elucidate applicability of ovalbumin (OVA) as depressant for pyrite. The synergetic effect of metal ions in addition to its possible use in case of accidental activation by metal ions. CV tests stated that OVA adsorbed irreversibly on pyrite, and restricted electron transfer up to moderately oxidizing potentials due to electrostatic interaction together with weak hydrophobic interactions. At highly oxidizing potentials, adsorption occurred through electrochemical mechanisms through formation of metal-OVA chelates. Rate of pyrite depression with OVA was found to be potential dependent reaching its peak point around moderately oxidizing potentials both in absence and presence of metal ions. Electrochemically active metals display synergetic effect with OVA on pyrite depression, whereas noble metals activate pyrite and reduced depressing potency of OVA.