The COVID-19 pandemic highlights the need for rapid protein detection and quantification at the single-molecule level in a format that is simple and robust enough for widespread point-of-care applications. We here introduce a modular nanobody-organic electrochemical transistor architecture that enables the fast and specific detection and quantification of single-molecule to nanomolar protein antigen concentrations in complex bodily fluids. The sensor combines a new solution-processable organic semiconductor material in the transistor channel with the high-density and orientation-controlled bioconjugation of nanobody fusion proteins on disposable gate electrodes. It provides results after a 10 minutes exposure to 5 µL of unprocessed samples, maintains high specificity and single-molecule sensitivity in human saliva or serum, and is rapidly reprogrammed towards any protein target for which nanobodies exist. We demonstrate the use of this highly modular platform for the detection of green fluorescent protein, SARS-CoV-1/2, and MERS-CoV spike proteins and validate the sensor for COVID-19 screening in unprocessed clinical nasopharyngeal swab and saliva samples.