The COVID-19 pandemic has had a profound impact on people’s lives, making accurate prediction of epidemic trends a central focus in COVID-19 research. This study innovatively utilizes a spatiotemporal heterogeneity analysis (GTNNWR) model to predict COVID-19 deaths, simulate pandemic prevention scenarios, and quantitatively assess their preventive effects. The results show that the GTNNWR model exhibits superior predictive capacity to the conventional infectious disease dynamics model (SEIR model), which is approximately 9% higher, and reflects the spatial and temporal heterogeneity well. In scenario simulations, this study established five scenarios for epidemic prevention measures, and the results indicate that masks are the most influential single preventive measure, reducing deaths by 5.38%, followed by vaccination at 3.59%, and social distancing mandates at 2.69%. However, implementing single stringent preventive measures does not guarantee effectiveness across all states and months, such as California in January 2025, Florida in August 2024, and March–April 2024 in the continental U.S. On the other hand, the combined implementation of preventive measures proves 5 to-10-fold more effective than any single stringent measure, reducing deaths by 27.2%. The deaths under combined implementation measures never exceed that of standard preventive measures in any month. The research found that the combined implementation of measures in mask wearing, vaccination, and social distancing during winter can reduce the deaths by approximately 45%, which is approximately 1.5–3-fold higher than in the other seasons. This study provides valuable insights for COVID-19 epidemic prevention and control in America.