The Met Office has warned of ‘persistent’ rain and a risk of flooding from 6pm on Saturday to 5pm on Sunday.
Cities including Sheffield, Leeds, Manchester, Liverpool, Bangor, Swansea and Cardiff are covered by the weather warning.
Met Office meteorologist Alex Burkill said: "We have got a deep area of low pressure that will bring heavy and persistent rain, and strong winds too.
"In terms of rainfall totals, the greatest amounts could be up to 70mm. That will be over the hills and mountains.
"Away from there, some places could see 30mm to 40mm in a short space of time."
He said there is ‘likely’ to be some disruption to travel over the weekend, with ‘lots of spray on the roads’.
Mr Burkill said large waves and high spring tides could also increase the risk of ‘coastal impact’ in south-west England.
The weather warning has already led to the cancellation of the inaugural Regatta London race, which was due to take place on the River Thames on Sunday.
Organisers said they were unable to safely run the event due to ‘stormy weather’ affecting the river's water quality.
The Met Office said there will be sunny spells and showers across England and Wales on Saturday morning, before the worst of the weather arrives later in the evening.
Meteorologist Luke Miall said thunder and gusts of up to 30mph are forecast for Sunday.
Temperatures are forecast to reach highs of 19C on both days.
Mr Miall said wind and rain is forecast for England, Wales, Northern Ireland and southern Scotland throughout most of Sunday.