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Ephemeral rivers act as linear oases in drylands providing key resources to people and wildlife. However, not much is known about these rivers’ sensitivities to human activities. We investigated the landscape-level determinants of riparian tree dieback along the Swakop River, a dammed ephemeral river in Namibia, focusing on the native ana tree (Faidherbia albida) and the invasive mesquite (Prosopis spp.). We surveyed over 1,900 individual trees distributed across 24 sites along a 250 km stretch of the river. General linear mixed models were used to test five hypotheses relating to three anthropogenic threats: river flow disruption from damming, human settlement and invasive species. We found widespread dieback in both tree populations: 51% mortality in ana tree, with surviving trees exhibiting 18% canopy death (median); and 26% mortality in mesquite, with surviving trees exhibiting 10% canopy death. Dieback in the ana tree was most severe where trees grew on drier stretches of the river, where tributary flow was absent and where mesquite grew more abundantly. Dieback in the mesquite, a more drought-tolerant taxon, did not show any such patterns. Our findings suggest that dieback in the ana tree is primarily driven by changes in river flow resulting from upstream dam creation and that tributary flows provide a local buffer against this loss of main channel flow. The hypothesis that the invasive mesquite may contribute to ana tree dieback was also supported. Our findings suggest that large dams along the main channels of ephemeral rivers have the ability to cause widespread mortality in downstream riparian trees. To mitigate such impacts, management might focus on the maintenance of natural tributary flows to buffer local tree populations from the disruption to main channel flow.