The Met Office’s highest warning covers an area including London, Manchester and York on Monday and Tuesday.
It means there is a risk to life and daily routines will need to change.
Speed restrictions are likely on railway lines, some schools will close early and some hospital appointments will be cancelled.
On the roads, gritters are planning to spread sand to reduce melting, and the RAC has warned more drivers will need help as cars overheat.
On top of the Met Office warning, the UK Health Security Agency issued its highest level four heat alert to health and care bodies – warning illness and death could occur “among the fit and healthy”.
NHS leaders on Friday evening warned there would be greater demand for ambulances and patients could be at risk if left outside hospitals in emergency vehicles in hot weather.
In a letter they said ambulances should not wait outside emergency departments more than 30 minutes before offloading patients.
It is the first time a red heat warning has been issued for parts of the UK, although the extreme heat warning system was only introduced in 2021.
Downing Street said the alert was being treated as a national emergency. Officials met on Friday and will meet again during the weekend to discuss the response.
The weather at the start of next week is forecast to be warm across the UK but temperatures will be more like 30C in Scotland and Northern Ireland, rather than the high 30s predicted in parts of England and Wales.
The heatwave – originating in north Africa – is spreading across Europe and has fuelled wildfires in Portugal, France and Spain.
Met Office spokesman Grahame Madge said it was “potentially a very serious situation”, with a 50% chance of temperatures reaching 40C – likely along the A1 corridor, running from London northwards towards Yorkshire and the North East.
The highest recorded temperature in the UK was 38.7C in Cambridge in 2019 and BBC Weather presenter Matt Taylor said there is now a realistic possibility of hitting 40C in the UK.
“That is exceptionally hot, the sort of temperatures that if you are on holiday you may be able to deal with but in day-to-day life it can have severe impacts on health,” he said.