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Urgent response to the coronavirus disease 2019 (COVID-19) pandemic necessitated rapid implementation of experimental, re-purposed, or off-label treatment strategies, which can be monitored via active surveillance (AS). Using a scoping review methodology, we summarized AS systems used to assess the safety and effectiveness of health products for COVID-19 treatment. We searched electronic databases (MEDLINE, Embase, Web of Science, and Cochrane Library), global regulatory agency websites, and registries, and implemented alerts until August 2022. The records with data source, active data access, and timely reporting that were applied in COVID-19 treatment were considered eligible. Fifteen publications to describe 13 AS systems were identified from a total of 9,183 literature records. Six systems were designed for safety, one for effectiveness, three for both, and three provided descriptive treatment data. Eleven systems were repurposed, and two were created during the pandemic. Twelve were initiated for COVID-19 in 2020, and one existing system was applied for a safety study in 2022. Various data sources, technical tools, procedures, and study designs were applied to provide active data access and timely analyses of safety and effectiveness of antivirals, antibiotics, hydroxychloroquine, corticosteroid, and others used for COVID-19. The COVID-19 pandemic accelerated the development and repurposing of AS to address urgent challenges in evaluating the safety and effectiveness of therapeutic interventions. In this scoping review, we highlight the essential role of AS in generating timely real-world evidence, supporting clinical and regulatory decision-making, and contributing to healthcare system resilience. The findings also reveal gaps in transparency and standardization, highlighting the need for integrated, ethically governed AS infrastructures that support data privacy, public trust, and timely evidence generation for future public health emergencies.