Medicine safety monitoring in Sub-Saharan Africa faces persistent challenges due to fragmented pharmacovigilance (PV) systems, weak stakeholder coordination, and a shortage of trained professionals. The PROFORMA project (2018–2024) aimed to strengthen PV infrastructure, post-marketing surveillance, and clinical trial regulatory capacities in Ethiopia, Kenya, Rwanda, and Tanzania. A comprehensive baseline assessment conducted across national medicines regulatory authorities (NMRAs), public health programs, health facilities, and marketing authorization holders revealed significant gaps in policy, legislation, infrastructure, coordination, and risk management. To address these issues, the project implemented the PROFORMA-Triangle Model—a trilateral collaboration among academia, NMRAs, and public health programmes. Country-specific interventions included policy reforms, capacity building, and workforce development. PV was integrated into academic curricula; regulatory staff received postgraduate training; and a range of short courses and e-learning modules were developed. Using a train-the-trainer cascade model, over 40,000 stakeholders were trained, significantly expanding PV capacity across the region. The project led to substantial improvements in PV and post-marketing surveillance systems, enhancing policies, guidelines, coordination mechanisms, risk management strategies, and communication. PROFORMA generated over 25 peer-reviewed studies that highlighted critical PV challenges and supported evidence-based policy reforms. PV education was institutionalized through university programmes and digital platforms, while the scalable Triangle Model promoted cross-sector collaboration. Twelve postgraduate experts (six PhDs, six MScs) were trained and now lead PV initiatives and regulatory institutions. Rwanda’s FDA achieved WHO Maturity Level 3 status, with Ethiopia and Kenya approaching the same level, and Tanzania targeting Level 4. In conclusion, the PROFORMA project has developed a sustainable, replicable framework for strengthening PV systems in resource-limited settings. Its integrated training programmes, governance models, and expert workforce offer a scalable solution for improving medicine safety in sub-Saharan Africa and similar contexts.