The Mekong delta is Vietnam’s premier rice-growing region, forming the livelihood basis for millions of farmers. At the same time, the region is facing various challenges, ranging from extreme weather events, saline water intrusion, and other anthropogenic pressures. This study examines how saline water intrusion and drought have affected rice yield in the Vietnamese Mekong Delta (VMD). Applying the Standardized Precipitation Index (SPI) and the maximum and minimum values of annual average salinity, we spatially examine the effects of drought and saline water intrusion on rice yields over a 40-year period (1980–2019). Our results highlight that 42% of the natural land area of the VMD has experienced increased drought occurred during the winter-spring (WS) rice cropping season, while certain inland regions have additionally experienced increased drought occurred during the summer-autumn (SA) rice cropping season. The Tri Ton Station, which has a significant Sen’s slope of −0.025 and a p-value of 0.05, represents an upstream semi-mountainous part of the delta, indicative of a rising severity of reoccurring drought. It should be noted that the yield decreases during the summer-autumn season as the positive SPI_SA increases. Salinity, on the other hand, is associated with SPI_WS during the winter-spring season. Our results highlight the need for improved evidence-based planning and investments in priority adaptation for both sustainable water infrastructure and improved system resilience.