The city recorded 1,389.1 deaths per 100,000 people last year, against a UK average of 982.5.
The Scottish council areas of West Dunbartonshire and North Lanarkshire also ranked high up the list, with 1,300.9 and 1,300.6 deaths per 100,000 respectively.
The data, compiled by the Office for National Statistics (ONS), showed that Blackpool had the highest mortality rate of any council area in England, with 1,287.8 deaths per 100,000, closely followed by Middlesbrough, with 1,285.4.
Apart from the City of London, the London borough of Kensington and Chelsea had the lowest mortality rate of any area of the UK, with just 667.4 deaths per 100,000.
n Wales, Blaenau Gwent had the highest mortality rate of any area, with 1,234.8 deaths per 100,000 people, and Monmouthshire had the lowest, with 872.6.
Belfast also recorded the highest mortality rate for Northern Ireland, with 1,139.3 deaths per 100,000, while Causeway Coast and Glens had the lowest, with 918.4.
The figures, taken from registered deaths in the UK in 2016, showed that Scotland recorded the most deaths of any UK nation, with an average 1,136.4 deaths per 100,000 people, followed by Wales (1,045.7) and Northern Ireland (1,015.9).
England recorded the lowest number of deaths on average, with 959.8 deaths per 100,000 people - slightly above the UK average of 982.5.
The “substantial variation in mortality rates between different local areas reflects underlying differences in factors such as income deprivation, socio-economic position and health behaviour,” the ONS said.