The presentation highlights the African Union Smart Safety Surveillance (AU-3S) initiative’s efforts to strengthen vaccine safety monitoring across Africa during the COVID-19 pandemic. It details how AU-3S collaborated with national regulatory authorities (NRAs), EPIs, and partners like MHRA to build a centralized, continent-wide pharmacovigilance system. Through the deployment of digital tools like the Med Safety App and the Data Integration and Signal Detection (DISD) system, AU-3S enabled real-time data collection, signal detection, and evidence-based decision-making. The Joint Signal Management (JSM) Group facilitated cross-country analysis and regulatory action, with over 56,000 AEFI reports integrated and multiple items of interest identified. The pilot demonstrated Africa’s capacity to lead its own safety surveillance, improve coordination, and lay the groundwork for future expansion to more countries and disease areas, ultimately aiming to establish a fully African-owned safety platform.