A once-in-a-century global public health crisis, the COVID-19 pandemic has damaged human health and world economy greatly. To help combat the virus, we report a self-resetting molecular probe capable of repeatedly detecting SARS-CoV-2 RNA, developed by orchestrating a fuel dissipative system via DNA nanotechnology. A set of simulation toolkits was utilized to design the probe, permitting highly consistent signal amplitudes across cyclic detections. Uniquely, full width at half maximum regulated by dissipative kinetics exhibits a fingerprint signal suitable for high confidential identifications of single-nucleotide variants. Further examination on multiple human-infectious RNA viruses, including ZIKV, MERS-CoV, and SARS-CoV, demonstrates the generic detection capability and superior orthogonality of the probe. It also correctly classified all the clinical samples from 55 COVID-19 patients and 55 controls. Greatly enhancing the screening capability for COVID-19 and other infectious diseases, this probe could help with disease control and build a broader global public health agenda. (c) 2021 Elsevier Ltd. All rights reserved.