The Zambezi River Basin in southern Africa is relatively undeveloped from both a hydropower and irrigated agriculture perspective, despite the existence of the large Kariba and Cahora Bassa dams. Accelerating economic growth increases the potential for competition for water between hydropower and irrigated agriculture, and climate change will add additional stresses to this system. The objective of this study was to assess the vulnerability of major existing and planned new hydropower plants to changes in climate and upstream irrigation demand. Our results show that Kariba is highly vulnerable to a drying climate, potentially reducing average electricity generation by 12 %. Furthermore, the expansion of Kariba generating capacity is unlikely to deliver the expected increases in production even under a favourable climate. The planned Batoka Gorge plant may also not be able to reach the anticipated production levels from the original feasibility study. Cahora Bassa’s expansion is viable under a wetting climate, but its potential is less likely to be realised under a drying climate. The planned Mphanda Nkuwa plant can reach expected production levels under both climates if hydropower is given water allocation priority, but not if irrigation is prioritised, which is likely. For both Cahora Bassa and Mphanda Nkuwa, prioritising irrigation demand over hydropower could severely compromise these plants’ output. Therefore, while climate change is the most important overall driver of variation in hydropower potential, increased irrigation demand will also have a major negative impact on downstream plants in Mozambique. This implies that climate change and upstream development must be explicitly incorporated into both project and system expansion planning.