Critics suggested the capital's Mayor was shirking his duties by flying to Morocco for a mini-break.
And other senior politicians including Theresa May and Sajid Javid are also under pressure for failing to crack down on knife violence.
The Home Secretary was accused of paying "lip service" to the crisis – without doing anything to stop it by boosting police numbers.
Two 17-year-olds were murdered over the weekend – Jodie Chesney in East London, and Yousef Ghaleb Makki in Greater Manchester.
A total of 20 homicides have been carried out in the capital so far this year.
The Sun revealed today that Mr Khan has gone on holiday to Marrakech with his wife for a three-day break.
Asked about the Mayor's holiday on LBC, Health Secretary Matt Hancock said: "I'm pretty surprised.
"There are moments of crisis where if you're in a big job with heavy responsibilities you need to be there and acting.
"I think there's an awful lot that Sadiq Khan needs to be doing on knife crime here in London to keep people safe."
If you're in a big job with heavy responsibilities you need to be there and acting
Susan Hall, a Tory member of the London Assembly, told The Sun: “It is deeply shocking but hardly surprising that the Mayor has jetted off on holiday at a time when London’s crime epidemic rages on.
"This really does sum up Sadiq Khan’s complacent attitude towards spiralling violent crime rates in our city."
The row is similar to when the previous Mayor, Boris Johnson, stayed on a family holiday during the 2011 London riots.
Cabinet ministers also face demands to step up the fight against knife crime by increasing police funding.
Shadow Home Secretary Diane Abbott today said the epidemic was "spiralling out of control" and hit out at cuts to police numbers.
She added: “Labour advocates what works – a public health approach to knife crime, which has produced results in Glasgow. The Home Secretary has himself paid lip service to the idea, but has taken no effective action to deliver it."
Lib Dem ex-minister Ed Davey blasted: "Time Javid admitted May’s huge police cuts are a big part of the problem."
Labour MP Sarah Jones added: "I will be calling on the Prime Minister this week to take personal charge of the knife crime crisis."
Police are looking for two suspects over the death of Jodie Chesney, who was killed in a park in Romford on Friday night.
Mr Javid is today meeting a group of senior police chiefs to discuss how to crack down on the violence.
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