BackgroundFrom January 2020 to June 2022, strict interventions against COVID-19 were implemented in Guangdong Province, China. However, the evolution of COVID-19 dynamics remained unclear in this period.ObjectivesThis study aims to investigate the evolution of within- and between-city COVID-19 dynamics in Guangdong, specifically during the implementation of rigorous prevention and control measures. The intent is to glean valuable lessons that can be applied to refine and optimize targeted interventions for future crises.MethodsData of COVID-19 cases and synchronous interventions from January 2020 to June 2022 in Guangdong Province were collected. The epidemiological characteristics were described, and the effective reproduction number (Rt) was estimated using a sequential Bayesian method. Endemic-epidemic multivariate time-series model was employed to quantitatively analyze the spatiotemporal component values and variations, to identify the evolution of within- and between-city COVID-19 dynamics.ResultsThe incidence of COVID-19 in Guangdong Province was 12.6/100,000 population (15,989 cases) from January 2020 to June 2022. The Rt predominantly remained below 1 and increased to a peak of 1.39 in Stage 5. As for the evolution of variations during the study period, there were more spatiotemporal components in stage 1 and 5. All components were fewer from Stage 2 to Stage 4. Results from the endemic-epidemic multivariate time-series model revealed a strong follow-up impact from previous infections in Dongguan, Guangzhou and Zhanjiang, with autoregressive components of 0.48, 0.45 and 0.36, respectively. Local risk was relatively high in Yunfu, Shanwei and Shenzhen, with endemic components of 1.17, 1.04 and 0.71, respectively. The impact of the epidemic on the neighboring regions was significant in Zhanjiang, Shenzhen and Zhuhai, with epidemic components of 2.14, 1.92, and 1.89, respectively.ConclusionThe findings indicate the presence of spatiotemporal variation of COVID-19 in Guangdong Province, even with the implementation of strict interventions. It’s significant to prevent transmissions within cities with dense population. Preventing spatial transmissions between cities is necessary when the epidemic is severe. To better cope with future crises, interventions including vaccination, medical resource allocation and coordinated non-pharmaceutical interventions were suggested.