Parts of Hampshire, Berkshire, Buckinghamshire and Sussex will move into Tier 3, the Health Secretary Matt Hancock has announced.
Speaking in the House of Commons, Mr Hancock said coronavirus cases across the South East had risen by 46% in the last week, with hospital admissions up by more than a third.
Portsmouth, Gosport, Havant, Berkshire, Buckinghamshire, Surrey, with the exception of Waverley, Hastings and Rother will go into the highest tier from Saturday.
Mr Hancock told MPs: "As we enter the coldest months we must be vigilant and keep this virus under control."
Kent and Medway remain in Tier 3, the highest tier, following a spike in coronavirus infections.
The rest of the region will stay in Tier 2, apart from the Isle of Wight which remains in Tier 1.
The latest change means from Saturday a total of 38 million people will be living under the toughest Covid restrictions - 68% of the population of England.
What does Tier 3 mean?
In Tier 3, you cannot meet socially indoors with anyone not in your household or support bubble. You can meet in some outdoor public spaces including parks and beaches, but you must follow the rule of six.
Pubs, cafes and restaurants must close unless they have a takeaway service and all indoor hospitality venues including hotels and B&Bs must also close.
However, in all tiers and across England, shops, gyms and personal care services, like hairdressers, can all remain open. But group exercise classes should not go ahead indoors.
Communal worship, weddings and outdoor sports will continue. The rule of six will apply in outdoor public spaces like parks, beaches or public gardens.
ITV News Meridian's Juliette Fletcher reports on the reaction in Reading
Meanwhile Lib Dem leader of Portsmouth City Council, Gerald Vernon-Jackson, says he is disappointed that the city is going into Tier 3 but that he is 'not surprised'.
He says: "I'm told that one of the big reasons is because there's big problems at QA hospital in Portsmouth, which doesn't just serve Portsmouth, but the surrounding area. And we've got to protect the hospital to make sure that it's got the capacity to look after people.
"It is illogical that Southwick, at the top of the hill, is in Tier 2, that Portchester is in Tier 2, but Gosport, Havant and Portsmouth are in Tier 3. It's not logical."
It comes as Prime Minister Boris Johnson insisted he did not want to “cancel” Christmas, but said people should prepare for a “smaller, safer” festive period amid fears about the spread of coronavirus.
Confirming the so-called “Christmas window” allowing three households to join together between December 23 and 27 would go ahead, Mr Johnson said people would be left to make individual judgments on whether Christmas celebrations were worth the risk, with warnings to avoid elderly relatives and a recommendation to isolate beforehand.