Brazil experienced one of the fastest increasing numbers of coronavirus disease (COVID-19) cases worldwide. The Sao Paulo State (SPS) reported a high incidence, particularly in Sao Paulo municipality. This study aimed to identify clusters of incidence and mortality of hospitalized patients with severe acute respiratory syndrome for COVID-19 in the SPS, in 2020-2021, and describe the origin flow pattern of the cases. Cases and mortality risk area clusters were identified through different analyses (spatial clusters, spatio-temporal clusters, and spatial variation in temporal trends) by weighting areas. Ripley's K12-function verified the spatial dependence between the cases and infrastructure. There were 517,935 reported cases, with 152,128 cases resulting in death. Of the 470,441 patients hospitalized and residing in the SPS, 357,526 remained in the original municipality, while 112,915 did not. Cases and death clusters were identified in the Sao Paulo metropolitan region (SPMR) and Baixada Santista region in the first study period, and in the SPMR and the Campinas, Sao Jose do Rio Preto, Barretos, and Sorocaba municipalities during the second period. We highlight the priority areas for control and surveillance actions for COVID-19, which could lead to better outcomes in future outbreaks.