<p>Malaria remains a global health challenge due to the emergence and spread of drug-resistant strains, highlighting the urgent need for the development of new treatments. Gold(I) hybrids, [AuCQPQ]⁺ (<b>Auhyb1</b>) and [AuAQPQ]⁺ (<b>Auhyb2</b>), incorporating chloroquine (CQ), amodiaquine (AQ), and primaquine (PQ), exhibited potent antiplasmodial activity by disrupting hemozoin formation, likely through ferriheme binding. To elucidate these interactions, we employed molecular dynamics and DFT calculations to assess binding conformations and energies. Results indicate that protonated <b>Auhyb1</b> forms a clamp-type structure around ferriheme, stabilizing the formed complex via strong H-bonds and π–π stacking. Such interactions reflect a decrease in enthalpy, while the gold ion presence induces an entropy effect also favoring the association with ferriheme. <b>Auhyb2</b>, in contrast, interacts through AQ’s alcohol group coordination to iron, alongside H-bonding and π–π interactions, forming a stable alkoxide metal complex. These molecular interactions could enhance the antimalarial efficacy of conventional low-cost aminoquinoline drugs contributing to disrupt hemozoin crystallization in malaria’s parasite.</p> Graphical abstract <p></p>