The amber alert, which covers southeast England, the West Midlands, East Midlands, east of England and the southwest, means there is a greater risk to everyone’s health – and not just the vulnerable.
“There is a high likelihood that forecasted temperatures will be reached rapidly over the weekend in these regions, while we are also likely to see high overnight temperatures,” the UK Health Security Agency said.
A “plume of warm air” from the south is expected to push the mercury up, the Met Office says, with a chance of 30C for some parts of England.
Those areas could be hotter than Ibiza and Milan, where temperatures will reach 28C.
An amber alert indicates the effects are likely to be felt across the whole health service, and the wider population could suffer, not just the most vulnerable.
A yellow alert has also been issued for the northeast, northwest and Yorkshire and Humber regions of England. London remains at this level.
Both alerts cover 9am on Friday to 9am on Monday.
The alerts have been issued under a new colour-coded warning system for heatwaves, launched by the agency and the Met Office.
The Met Office has also issued a thunderstorm warning, running from 2pm to 9pm on Saturday, in cities including Manchester, Cardiff and London.
The weekend’s high temperatures are expected to trigger showers, some of which could be “torrential and thundery”, with more than 30-40mm potentially falling within an hour.
Rain, hail, wind and lightning are also predicted to hit some areas, although others parts of the country will see no rain at all.
Oliver Clayden, from the Met Office, said there could be some travel disruption over the weekend.
He said: “After a prolonged dry spell there is a chance of surface water flooding.
“There could be some surface water issues that could cause travel disruptions as well as the high gusts across parts of the country.”
Mr Clayden added: “This is going to be the warmest weekend of the year, which is to be expected as we go into summer.
“This weekend will also see hail mixed in with strong gusts of wind and rain hit parts of the country.”