Even entering the third year of the COVID-19 pandemic, only a small number of COVID-19 antiviral drugs are approved. Curcumin has previously shown antiviral activity against SARS-CoV-2 nucleocapsid, but its poor bioavailability limits its clinical uses. Utilizing nanotechnology structures, curcumin-derived carbon-dots (cur-CDs) were synthesized to increase low bioavailability of curcumin. analyses were performed using molecular docking, inhibition of SARS-CoV-2 nucleocapsid C-terminal domain (N-CTD) and antiviral activity were assessed in dimer-based screening system (DBSS) and respectively. Curcumin bound with the N-CTD at ΔG = -7.6 kcal/mol, however modifications into cur-CDs significantly improved the binding affinity and %interaction. Cur-CDs also significantly increased protection against SARS-CoV-2 in both DBSS and at MOI = 0.1. This study demonstrated the effect of post-infection treatment of curcumin and novel curcumin-derived carbon-dots on SARS-CoV-2 N-CTD dimerization. Further investigation on pre-infection and treatment of curcumin and cur-CDs are required for a comprehensive understanding on the carbon-dots enhanced antiviral activity of curcumin against SARS-CoV-2.