Background Natural language processing (NLP) of unstructured text from electronic medical records (EMR) can improve the characterization of COVID-19 signs and symptoms, but large-scale studies demonstrating the real-world application and validation of NLP for this purpose are limited. Objective The aim of this paper is to assess the contribution of NLP when identifying COVID-19 signs and symptoms from EMR. Methods This study was conducted in Kaiser Permanente Southern California, a large integrated health care system using data from all patients with positive SARS-CoV-2 laboratory tests from March 2020 to May 2021. An NLP algorithm was developed to extract free text from EMR on 12 established signs and symptoms of COVID-19, including fever, cough, headache, fatigue, dyspnea, chills, sore throat, myalgia, anosmia, diarrhea, vomiting or nausea, and abdominal pain. The proportion of patients reporting each symptom and the corresponding onset dates were described before and after supplementing structured EMR data with NLP-extracted signs and symptoms. A random sample of 100 chart-reviewed and adjudicated SARS-CoV-2–positive cases were used to validate the algorithm performance. Results A total of 359,938 patients (mean age 40.4 [SD 19.2] years; 191,630/359,938, 53% female) with confirmed SARS-CoV-2 infection were identified over the study period. The most common signs and symptoms identified through NLP-supplemented analyses were cough (220,631/359,938, 61%), fever (185,618/359,938, 52%), myalgia (153,042/359,938, 43%), and headache (144,705/359,938, 40%). The NLP algorithm identified an additional 55,568 (15%) symptomatic cases that were previously defined as asymptomatic using structured data alone. The proportion of additional cases with each selected symptom identified in NLP-supplemented analysis varied across the selected symptoms, from 29% (63,742/220,631) of all records for cough to 64% (38,884/60,865) of all records with nausea or vomiting. Of the 295,305 symptomatic patients, the median time from symptom onset to testing was 3 days using structured data alone, whereas the NLP algorithm identified signs or symptoms approximately 1 day earlier. When validated against chart-reviewed cases, the NLP algorithm successfully identified signs and symptoms with consistently high sensitivity (ranging from 87% to 100%) and specificity (94% to 100%). Conclusions These findings demonstrate that NLP can identify and characterize a broad set of COVID-19 signs and symptoms from unstructured EMR data with enhanced detail and timeliness compared with structured data alone.