Abstract: BACKGROUND: The COVID-19 Delta variant has presented an unprecedented challenge to countries in Southeast Asia (SEA). Its transmission has shown spatial heterogeneity in SEA after countries have adopted different public health interventions during the process. Hence, it is crucial for public health authorities to discover potential linkages between epidemic progression and corresponding interventions such that collective and coordinated control measurements can be designed to increase their effectiveness at reducing transmission in SEA. OBJECTIVE: The purpose of this study is to explore potential linkages between the spatiotemporal progression of the COVID-19 Delta variant and nonpharmaceutical intervention (NPI) measures in SEA. We detected the space-time clusters of outbreaks of COVID-19 and analyzed how the NPI measures relate to the propagation of COVID-19. METHODS: We collected district-level daily new cases of COVID-19 from June 1 to October 31, 2021, and district-level population data in SEA. We adopted prospective space-time scan statistics to identify the space-time clusters. Using cumulative prospective space-time scan statistics, we further identified variations of relative risk (RR) across each district at a half-month interval and their potential public health intervention linkages. RESULTS: We found 7 high-risk clusters (clusters 1-7) of COVID-19 transmission in Malaysia, the Philippines, Thailand, Vietnam, and Indonesia between June and August, 2021, with an RR of 5.45 (P<.001), 3.50 (P<.001), 2.30 (P<.001), 1.36 (P<.001), 5.62 (P<.001), 2.38 (P<.001), 3.45 (P<.001), respectively. There were 34 provinces in Indonesia that have successfully mitigated the risk of COVID-19, with a decreasing range between -0.05 and -1.46 due to the assistance of continuous restrictions. However, 58.6% of districts in Malaysia, Singapore, Thailand, and the Philippines saw an increase in the infection risk, which is aligned with their loosened restrictions. Continuous strict interventions were effective in mitigating COVID-19, while relaxing restrictions may exacerbate the propagation risk of this epidemic. CONCLUSIONS: The analyses of space-time clusters and RRs of districts benefit public health authorities with continuous surveillance of COVID-19 dynamics using real-time data. International coordination with more synchronized interventions amidst all SEA countries may play a key role in mitigating the progression of COVID-19.