Policies supporting rice production and investments in water infrastructure enabled intensification and diversification of farming systems in the Vietnamese Mekong Delta (VMD) over the past 20 years. Yet, demands of food security, economic development, and climate change continue to pose diverging and often conflicting challenges for water resources management in the upper, central, and coastal zones of the delta. The major changes effected in the VMD’s hydrological regime and land-use patterns are acknowledged in the literature, but few studies have examined the interplay between these dynamics at the delta scale. Based on time-series maps and statistical data on land-use, flooding, and salinity intrusion, we investigated the interrelations between land-use dynamics and changes in hydrological regime across the VMD in three representative periods. Land-use was found to be highly variable, changing by 14.94% annually between 2001 and 2012. Rice cropping underwent the greatest change, evolving from single cropping of traditional varieties towards double and triple cropping of high-yielding varieties. Aquaculture remained stable after rapid expansion in the 1990s and early 2000s. Meanwhile, flooding and salinity intrusion were increasingly controlled by hydrological infrastructure erected to supply freshwater for agriculture. Effects of this infrastructure became particularly evident from 2001 to 2012. During this period, spatial and temporal impacts on flooding and salinity intrusion were found, which extended beyond the rice fields to affect adjacent lands and livelihood activities. Unforeseen effects will likely be aggravated by climate change, suggesting a need to rethink the scale of planning towards a more integrated hydrologic approach.