Deaths of Despair (DoD) are socially patterned fatalities encompassing those attributable to drug and alcohol misuse and suicide. DoD occur much more frequently in socially deprived communities. This ecological study aimed to yield new knowledge on the spatial distribution of DoD, and socioeconomic factors that predict DoD risk in England. Via ICD-10 coding, deaths nationally during 2019-2021 were classified to non-overlapping categories of drug-related death, alcohol-specific death, and suicide. The proportion of DoD from each of these causes was calculated and age standardised DoD rates were generated for local authorities. A multivariable regression model for DoD risk was developed using 25 socioeconomic indicators. In 2019-2021, an estimated 46,200 people lost their lives due to DoD. Rates were higher in the North and in coastal areas (p < 0.001), ranging regionally from 25.1/100,000 (SD 6.3) in London to 54.7/100,000 (SD 9.5) in the North East. Alcohol-specific deaths were the largest contributor of DoD, accounting for 44.1% (95%CI 43.5-44.8%) of all such deaths. Living in the North, unemployment, White British ethnicity, living alone, economic inactivity, employment in elementary occupations, and living in urban areas were significantly associated with elevated DoD risk. DoD in England are spatially patterned, with northern regions experiencing a much higher burden of mortality from these avoidable causes. This study provides novel insights into the area-level factors associated with DoD in England. Potential ecological error is a key limitation.