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Khan, a member of the opposition Labour Party, was elected to the influential position of mayor last May on a promise to stand up for the city's businesses. He has called for the government to avoid the uncertainty of a messy divorce from the EU, saying it would damage confidence in the city.
"It's deeply concerning that we still appear to have 'muddled thinking' at the heart of government so soon before the negotiations are set to start," Khan will say in a speech later on Thursday according to a statement from his office.
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His words echo those of Britain's former ambassador to the EU, Ivan Rogers, who resigned last week saying that Prime Minister Theresa May government was "muddled" in its approach. May refuted the suggestion, saying she would set out her strategy over the coming weeks.
"The only thing that would be as damaging as a hard Brexit is a muddled Brexit, and - unfortunately - it looks like that is where we are heading without urgent action," Khan is due to say.
He will reiterate his view that London needs preferential access to the single market, access to skilled workers in Europe and a transitional agreement with the EU to smooth the Brexit process.
Khan will also restate his case for London to have more control over its economy policy. He will promise to compile his own industrial strategy for London to feed into the government's plan to reshape the British economy.
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May has promised to draw up an industrial strategy that will revive areas of the country which have suffered from a decades-long decline in manufacturing, to try to both rebalance the services-reliant economy and re-engage with disillusioned working-class voters.
"We need more control of the right levers to improve competitiveness, stimulate growth and invest in our long-term future," Khan will say. "If we want an industrial strategy that works for London and therefore for Britain, we must have more control.”
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