City Hall said Covid-19 cases in London had exceeded 1,000 per 100,000, while there are 35% more people in hospital with the virus than in the peak of the pandemic in April.
A “major incident” means the “severity of the consequences” associated with it are “likely to constrain or complicate the ability of responders to resource and manage the incident”.
Mr Khan has written to the Prime Minister Boris Johnson asking for more financial support for Londoners who need to self-isolate and unable to work, and for daily vaccination data.
He is also asking for the closure of places of worship and for face masks to be worn routinely outside of the home, including in crowded places and supermarket queues.
Mr Khan said: “The situation in London is now critical with the spread of the virus out of control.
“The number of cases in London has increased rapidly with more than a third more patients being treated in our hospitals now compared to the peak of the pandemic last April.
“Our heroic doctors, nurses and NHS staff are doing an amazing job, but with cases rising so rapidly, our hospitals are at risk of being overwhelmed. The stark reality is that we will run out of beds for patients in the next couple of weeks unless the spread of the virus slows down drastically.
“We are declaring a major incident because the threat this virus poses to our city is at crisis point. If we do not take immediate action now, our NHS could be overwhelmed and more people will die.
“Londoners continue to make huge sacrifices and I am today imploring them to please stay at home unless it is absolutely necessary for you to leave. Stay at home to protect yourself, your family, friends and other Londoners and to protect our NHS.”
Earlier in the week, staff at St George’s Hospital say they are ‘overwhelmed’ and feel ‘demoralised’ as they battled the second wave of the pandemic.
An internal incident was also declared at Queen Elizabeth Hospital over the number of patients testing positive for Covid-19 being admitted to the site.