Therapeutic options for the highly pathogenic human coronavirus (HCoV) infections are urgently needed. Anti-coronavirus therapy is however challenging, as coronaviruses are biologically diverse and rapidly mutating. In this work, the antiviral activity of seven different carbon quantum dots (CQDs) for the treatment of human coronavirus HCoV-229E infections was investigated. The first generation of antiviral CQDs was derived by hydrothermal carbonization from ethylenediamine/citric acid as carbon precursors and post-modified with boronic acid ligands. These nanostructures showed a concentration dependent virus inactivation with an estimated EC50 of 52±8 µg mL-1. CQDs derived from 4-aminophenylboronic acid without any further modification resulted in the second-generation of anti-HCoV nanomaterials with an EC50 lowered to 5.2±0.7 µg mL-1. The underlying mechanism of action of these CQDs revealed to be inhibition of HCoV-229E entry that could be due to interaction of the functional groups of the CQDs with HCoV-229E entry receptors; surprisingly, an equally large inhibition activity was observed at the viral replication step.