question: The COVID‐19 pandemic caused by SARS‐CoV‐2 is threating global health Inhibiting interaction of the receptor‐binding domain of SARS‐CoV‐2 S protein (SRBD) and human ACE2 receptor is a promising treatment strategy However, SARS‐CoV‐2 neutralizing antibodies are compromised by their risk of antibody‐dependent enhancement (ADE) and unfavorably large size for intranasal delivery To avoid these limitations, we demonstrated an aptamer blocking strategy by engineering aptamers’ binding to the region on SRBD that directly mediates ACE2 receptor engagement, leading to block SARS‐CoV‐2 infection With aptamer selection against SRBD and molecular docking, aptamer CoV2‐6 was identified and applied to prevent, compete with, and substitute ACE2 from binding to SRBD CoV2‐6 was further shortened and engineered as a circular bivalent aptamer CoV2‐6C3 (cb‐CoV2‐6C3) to improve the stability, affinity, and inhibition efficacy cb‐CoV2‐6C3 is stable in serum for more than 12 h and can be stored at room temperature for more than 14 days Furthermore, cb‐CoV2‐6C3 binds to SRBD with high affinity (Kd=0 13 nM) and blocks authentic SARS‐CoV‐2 virus with an IC50 of 0 42 nM