Since its emergence in December 2019, the COVID-19 pandemic has resulted in a significant increase in deaths worldwide. This article presents a detailed analysis of the mortality burden of the COVID-19 pandemic across 569 regions in 25 European countries. We produce age and sex-specific excess mortality and present our results using Age-Standardised Years of Life Lost in 2020 and 2021, as well as the cumulative impact over the two pandemic years. Employing a forecasting approach based on CP-splines that considers regional diversity and provides confidence intervals, we find notable losses in 362 regions in 2020 (440 regions in 2021). Conversely, only seven regions experienced gains in 2020 (four regions in 2021). We also estimate that eight regions suffered losses exceeding 20 years of life per 1000 population in 2020, whereas this number increased to 75 regions in 2021. The contiguity of the regions investigated in our study also reveals the changing geographical patterns of the pandemic. While the highest excess mortality values were concentrated in the early COVID-19 outbreak areas during the initial pandemic year, a clear East-West gradient appeared in 2021, with regions of Slovakia, Hungary, and Latvia experiencing the highest losses. This research underscores the importance of regional analyses for a nuanced comprehension of the pandemic’s impact.