Sadiq Khan said Omicron is now the “dominant variant” in London and was having an impact on staff absences in the emergency services across the city.
He said London was the UK region with the largest number of Covid cases.
Latest government data shows there are 1,534 Covid patients in London hospitals – up 28.6% on last week.
Mr Khan said in the last 24 hours, London had seen the largest number of new cases since the coronavirus pandemic began – more than 26,000.
He added: “Hospital admissions are going up, but also staff absences are going up by a massive level.
“So I’ve taken the decision in consultation with our partners to declare a major incident today.”
Major incidents have previously been called in response to the Grenfell Tower fire in June 2017 and the terror attacks at Westminster Bridge and London Bridge.
A major incident is any emergency which requires the implementation of special arrangements by one or all of the emergency services, the NHS or the local authority.
It means the emergency services and hospitals cannot guarantee their normal level of response.
Mr Khan also declared a major incident on 8 January due to the rapid spread of Covid-19 and its impact on the health service.
It was in place until 26 February as case numbers in the capital fell.
Making the announcement on Saturday, Mr Khan said: “The really bad news is those in hospital – the vast, vast majority are unvaccinated that’s why it is so important to get both the vaccines and the booster jab.
“Londoners will notice over the course of the next few days even more places across the city offering both the vaccines and the booster.
“What we can’t afford to see is even more of our crucial key workers going off sick because they have this virus.”
Mr Khan’s comments came as Wembley Stadium, Stamford Bridge and The Valley were all set up as mass vaccination centres.
Oxford Street will also have a vaccination bus and Mr Khan urged people who were eligible to get a booster jab and for others to make sure they were vaccinated.
He said: “It is still the case that in some pockets of London, there are black Londoners, there are Muslim Londoners, there are Jewish Londoners, there are Eastern European Londoners, who still haven’t had a vaccine.
Latest government figures show 2.7m Londoners have received their booster jab.
Georgia Gould, chair of London Councils, said: “The rapid spread of Omicron across our city is of huge concern.
“Local councils have stepped up and played a vital role in supporting their communities through the pandemic. I know they will continue with these efforts, but we cannot do this alone.”
The mayor’s decision was announced as Cabinet ministers were set to be briefed on the latest Covid data.
On Friday, the UK saw another record number of daily Covid cases for the third consecutive day, with more than 93,000 infections confirmed.
But there were also a record 861,306 booster and third dose vaccine jabs administered – the highest daily total so far.
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