Background In response to COVID-19, Southeast Asian (SEA) countries had imposed stringent lockdowns and restrictions to mitigate the pandemic ever since 2019. Because of a gradually boosting vaccination rate along with a strong demand for economic recovery, many governments have shifted the intervention strategy from restrictions to ``Living with COVID-19’’ where people gradually resumed their normal activities since the second half of the year 2021. Noticeably, timelines for enacting the loosened strategy varied across Southeast Asian countries, which resulted in different patterns of human mobility across space and time. This thus presents an opportunity to study the relationship between mobility and the number of infection cases across regions, which could provide support for ongoing interventions in terms of effectiveness. Objective This study aimed to investigate the association between human mobility and COVID-19 infections across space and time during the transition period of shifting strategies from restrictions to normal living in Southeast Asia. Our research results have significant implications for evidence-based policymaking at the present of the COVID-19 pandemic and other public health issues. Methods We aggregated weekly average human mobility data derived from the Facebook origin and destination Movement dataset. and weekly average new cases of COVID-19 at the district level from 01-Jun-2021 to 26-Dec-2021 (a total of 30 weeks). We mapped the spatiotemporal dynamics of human mobility and COVID-19 cases across countries in SEA. We further adopted the Geographically and Temporally Weighted Regression model to identify the spatiotemporal variations of the association between human mobility and COVID-19 infections over 30 weeks. Our model also controls for socioeconomic status, vaccination, and stringency of intervention to better identify the impact of human mobility on COVID-19 spread. Results The percentage of districts that presented a statistically significant association between human mobility and COVID-19 infections generally decreased from 96.15% in week 1 to 90.38% in week 30, indicating a gradual disconnection between human mobility and COVID-19 spread. Over the study period, the average coefficients in 7 SEA countries increased, decreased, and finally kept stable. The association between human mobility and COVID-19 spread also presents spatial heterogeneity where higher coefficients were mainly concentrated in districts of Indonesia from week 1 to week 10 (ranging from 0.336 to 0.826), while lower coefficients were mainly located in districts of Vietnam (ranging from 0.044 to 0.130). From week 10 to week 25, higher coefficients were mainly observed in Singapore, Malaysia, Brunei, north Indonesia, and several districts of the Philippines. Despite the association showing a general weakening trend over time, significant positive coefficients were observed in Singapore, Malaysia, western Indonesia, and the Philippines, with the relatively highest coefficients observed in the Philippines in week 30 (ranging from 0.101 to 0.139). Conclusions The loosening interventions in response to COVID-19 in SEA countries during the second half of 2021 led to diverse changes in human mobility over time, which may result in the COVID-19 infection dynamics. This study investigated the association between mobility and infections at the regional level during the special transitional period. Our study has important implications for public policy interventions, especially at the later stage of a public health crisis.