Background Deaths during the COVID-19 pandemic result directly from infection and exacerbation of other diseases and indirectly from deferment of care for other conditions, and are socially and geographically patterned. We quantified excess mortality in regions of England and Wales during the pandemic, for all causes and for non-COVID-19 associated deaths. Methods Weekly mortality data for 1 Jan 2010 to 1 May 2020 for England and Wales were obtained from the Office of National Statistics. Mean-dispersion negative binomial regressions were used to model death counts based on pre-pandemic trends and exponentiated linear predictions were subtracted from: i) all-cause deaths; and ii) all-cause deaths minus COVID-19 related deaths for the pandemic period (07-13 March to 25 April to 8 May). Findings Between 7 March and 8 May 2020, there were 47,243 (95%CI: 46,671 to 47,815) excess deaths in England and Wales, of which 9,948 (95%CI: 9,376 to 10,520) were not associated with COVID-19. Overall excess mortality rates varied from 49 per 100,000 (95%CI: 49 to 50) in the South West to 102 per 100,000 (95%CI: 102 to 103) in London. Non-COVID-19 associated excess mortality rates ranged from -1 per 100,000 (95%CI: -1 to 0) in Wales (i.e. mortality rates were no higher than expected) to 26 per 100,000 (95%CI: 25 to 26) in the West Midlands. Interpretation The COVID-19 pandemic has had markedly different impacts on the regions of England and Wales, both for deaths directly attributable to COVID-19 infection and for deaths resulting from the national public health response.