To investigate climatic influence on floodplain trees, we analysed interannual correspondences between the Pacific Decadal Oscillation (PDO), river and groundwater hydrology, and growth and wood 13C discrimination (Δ13C) of narrowleaf cottonwoods (Populus angustifolia) in a semi-arid prairie region. From the Rocky Mountain headwaters, river discharge (Q) was coordinated with the PDO (1910–2008: r2 = 0.46); this pattern extended to the prairie and was amplified by water withdrawal for irrigation. Floodplain groundwater depth was correlated with river stage (r2 = 0.96), and the cottonwood trunk basal area growth was coordinated with current- and prior-year Q (1992–2008: r2 = 0.51), increasing in the mid-1990s, and decreasing in 2000 and 2001. Annual Δ13C decreased during low-flow years, especially in trees that were higher or further from the river, suggesting drought stress and stomatal closure, and male trees were more responsive than females (−0.86 versus −0.43‰). With subsequently increased flows, Δ13C increased and growth recovered. This demonstrated the linkages between hydroclimatic variation and cottonwood ecophysiology, and we conclude that cottonwoods will be vulnerable to drought from declining river flows due to water withdrawal and climate change. Trees further from the river could be especially affected, leading to narrowing of floodplain forests along some rivers.