Human serum transferrin (sTf) can also function as a noniron metal transporter since only 30% of it is typically saturated with a ferric ion. While this function of sTf can be fruitfully utilized for targeted delivery of certain metal therapeutics, it also runs the risk of trafficking the lethal radionuclides into cells. A large number of actinide (An) ions are known to bind to the iron sites of sTf although molecular-level understanding of their binding is unclear. Understanding the radionuclide interaction with sTf is a primary step toward future design of their decorporating agents since irrespective of the means of contamination, the radionuclides are absorbed and transported by blood before depositing into target organs. Here, we report an extensive multiscale modeling approach of two An (curium(III) and thorium(IV)) ions' binding with sTf at serum physiological pH. We find that sTf binds both the heavy ions in a closed conformation with carbonate as synergistic anions and the An-loaded sTf maintains its closed conformation even after 100 ns of equilibrium molecular dynamics (MD) simulations. MD simulations are performed in a polarizable water environment, which also incorporates electronic continuum corrections for ions via charge rescaling. The molecular details of the An coordination and An exchange free energies with iron in the interdomain cleft of the protein are evaluated through a combination of quantum mechanical (QM) and MD studies. In line with reported experimental observations, well-tempered metadynamics results of the ions' binding energetics show that An-sTf complexes are less stable than Fe-sTf. Additionally, curium(III) is found to bind more weakly than thorium(IV). The latter result might suggest relative attenuation of thorium(IV) cytotoxicity when compared with curium(III).