Cardiff and Swansea will go into local lockdown from 6pm on Sunday, the Welsh Government has said.
The southern town of Llanelli will go into local lockdown a day earlier, on Saturday at 6pm.
The new restrictions mean that about 1.5 million, or half of the Welsh population, will be under lockdown.
Under the new rules, people in the areas that have locked down cannot leave without a reasonable excuse. They will also not be able to meet indoors with anyone they do not live with.
Health minister Vaughan Gething told a press conference in Cardiff that people must work from home when possible.
On Thursday there were 25 new coronavirus cases in Carmarthenshire, where Llanelli is located, 39 in Cardiff and 41 in Swansea.
And Mr Gething warned people in Cardiff and Swansea not to have a “big blowout” over the weekend before restrictions come into force.
He said the Welsh government was acting on a more localised basis for the first time in Llanelli “because the transmission of coronavirus is concentrated on the town itself”, rather than Carmarthenshire as a whole.
“Introducing restrictions in any parts of Wales is always an incredibly difficult decision for us to make – having to introduce these restrictions in our biggest cities, including our capital, is another sombre milestone in a difficult year,” Mr Gething said.
“We’re acting to protect people’s health and to try and break the chain of transmission and stop the situation from getting worse.”
