Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has underscored an urgent need for rapid, accurate, and accessible diagnostic tools to detect infections, facilitate timely quarantine, and inform therapeutic decisions. Fabricating nanostructures on biosensors can enhance biomolecule orientation, minimize steric hindrance, and reduce non-specific binding, resulting in improved signal-to-noise ratios and high sensitivity, making them promising point-of-care diagnostic. However, clinical translation remains limited by challenges in scalable and reproducible fabrication and insufficient diagnostic validation. Here, we introduce a nanowell biosensor (NW-Biosen) fabricated via semiconductor manufacturing, enabling scalable production and yields >1000 electrodes with reproducible properties. NW-Biosen detects SARS-CoV-2 antigens from patient nasal swabs within ∼10 min, with high sensitivity and minimal interference from other coronavirus recombinant proteins, respiratory pathogens, bacteria, and environmental substances, while maintaining consistent reproducibility with different batches. We validated NW-Biosen through two independent clinical trials involving 249 retrospective and 243 prospective patient samples. In prospective cohort, NW-Biosen achieved 93.02% sensitivity, 98.73% specificity, and a Cohen's kappa of 0.927, indicating near-perfect agreement with RT-PCR and superior sensitivity compared to commercially available colorimetric kits. Thus, NW-Biosen enables rapid, highly sensitive, reproducible, and cost-effective at-home detection, with real-time data transmission to public health authorities via mobile app integrated with a miniature potentiostat.