This study examined the temporal and spatial patterns of hand, foot, and mouth disease (HFMD) in the Mekong Delta region in Vietnam. A time-series analysis was used to examine the temporal patterns of HFMD in relation to climate factors while a retrospective space-time scan was used to detect the high-risk space-time clusters of this disease. A 1 °C increase in average temperature was associated with 5.6% increase in HFMD rate at lag 5 days (95% CI 0.3–10.9). A 1% increase in humidity had equal influence of 1.7% increases on HFMD rate at both lag 3 days and 6 days (95% CI 0.7–2.7 and 95% CI 0.8–2.6, respectively). An increase in 1 unit of rainfall was associated with a 0.5% increase of HFMD rate on the lag 1 and 6 days (95% CI 0.2–0.9 and 95% CI 0.1–0.8, respectively). The predictive model indicated that the peak of HFMD was from October to December - the rainy season in the Mekong Delta region. Most high-risk clusters were located in areas with high population density and close to transport routes. The findings suggest that HFMD is influenced by climate factors and is likely to increase in the future due to climate change related weather events.