Background The COVID-19 pandemic has catalyzed a global public response and innovation in clinical study methods. Objective The COVID-19 Citizen Science study was designed to generate knowledge about participant-reported COVID-19 symptoms, behaviors, and disease occurrence. Methods COVID-19 Citizen Science is a longitudinal cohort study launched on March 26, 2020, on the Eureka Research Platform. This study illustrates important advances in digital clinical studies, including entirely digital study participation, targeted recruitment strategies, electronic consent, recurrent and time-updated assessments, integration with smartphone-based measurements, analytics for recruitment and engagement, connection with partner studies, novel engagement strategies such as participant-proposed questions, and feedback in the form of real-time results to participants. Results As of February 2021, the study has enrolled over 50,000 participants. Study enrollment and participation are ongoing. Over the lifetime of the study, an average of 59% of participants have completed at least one survey in the past 4 weeks. Conclusions Insights about COVID-19 symptoms, behaviors, and disease occurrence can be drawn through digital clinical studies. Continued innovation in digital clinical study methods represents the future of clinical research. International Registered Report Identifier (IRRID) DERR1-10.2196/28169