BACKGROUND: Resource allocation in health is universally challenging, but especially so in resource-constrained contexts in the Global South. Pursuing a strategy of evidence-based decision-making and using tools such as Health Technology Assessment (HTA), can help address issues relating to both affordability and equity when allocating resources. Three BRICS and Global South countries, China, India and South Africa have committed to strengthening HTA capacity and developing their domestic HTA systems, with the goal of getting evidence translated into policy. Through assessing and comparing the HTA journey of each country it may be possible to identify common problems and shareable insights. OBJECTIVES: This collaborative paper aimed to share knowledge on strengthening HTA systems to enable enhanced evidence-based decision-making in the Global South by: Identifying common barriers and enablers in three BRICS countries in the Global South; and Exploring how South-South collaboration can strengthen HTA capacity and utilisation for better healthcare decision-making. METHODS: A descriptive and explorative comparative analysis was conducted comprising a Within-Case analysis to produce a narrative of the HTA journey in each country and an Across-Case analysis to explore both knowledge that could be shared and any potential knowledge gaps. RESULTS: Analyses revealed that China, India and South Africa share many barriers to strengthening and developing HTA systems such as: (1) Minimal HTA expertise; (2) Weak health data infrastructure; (3) Rising healthcare costs; (4) Fragmented healthcare systems; and (5) Significant growth in non-communicable diseases. Stakeholder engagement and institutionalisation of HTA were identified as two conducive factors for strengthening HTA systems. CONCLUSION: China, India and South Africa have all committed to establishing robust HTA systems to inform evidence-based priority setting and have experienced similar challenges. Engagement among countries of the Global South can provide a supportive platform to share knowledge that is more applicable and pragmatic.