Leaving the European Union would leave the NHS facing a "real challenge", Jeremy Hunt has said.
In a warning that prompted claims of government scaremongering, the Health Secretary said the economic shock caused by Brexit could starve the cash-strapped health service of investment.
Some of the 100,000 foreign EU citizens on the workforce could also quit the country amid "uncertainties" over the status of visas and work permits, he said in the Observer.
Mr Hunt said he believed Britain would survive economically outside the bloc and would strike trade deals, but not without "years of economic uncertainty".
It would "inevitably mean less money for public services like the NHS", he wrote, in the latest intervention by a senior minister.
"Those who want to leave need to explain how they could protect the NHS from this economic shock," he said.
"No savings can compensate for the economic volatility that would follow a vote to leave.
"Another issue is the damage caused by losing some of the 100,000 skilled EU workers who work in our health and social care system. Uncertainties around visas and residency permits could cause some to return home, with an unpredictable impact on hard-pressed front-line services.
"Our doctors and nurses have never worked harder. Their passion and determination is to do the right thing for patients. Against that backdrop, Brexiteers need to be honest that a period of economic uncertainty and volatility poses a real challenge to the NHS."
Matthew Elliott, chief executive of Vote Leave, argued that Brexit would release funds to improve the NHS.
"Does this government's scaremongering know no bounds?" he asked.
"Under Jeremy Hunt's stewardship, the NHS has plummeted into a financial crisis.
"If we vote to leave we can stop wasting money on EU bureaucrats and instead spend our money on our priorities like the NHS."
Mr Hunt said those savings had been spent several times over in anti-EU campaigners' manifestos.
Stephen Dorrell, a Tory former health secretary and ex-chairman of the Commons health select committee, told the newspaper: "EU research programmes and single market legislation have greatly strengthened European co-operation in this area with substantial benefits for both healthcare and employment in the UK. It is a simple fact that Brexit would put all this at risk."
But Tory MP Stewart Jackson said: "Jeremy Hunt has to explain how uncontrolled EU migration and Turkish EU accession will help an overstretched NHS on his watch and afterwards."
Former cabinet minister Liam Fox said: "How many more colleagues will be forced into absurd and demeaning scare stories? Very sad."