"Economically and socially destructive" lockdowns are the only practical option until a Covid vaccine and better drugs are available, Chris Whitty has said.
England's chief medical officer rejected calls from some scientists to pursue "herd immunity" instead.
England is due to replace tiered regional restrictions with a four-week nationwide lockdown from Thursday.
It comes as the UK recorded a further 397 coronavirus deaths and 20,018 confirmed cases on Tuesday.
Meanwhile, more details of England's lockdown rules have also been revealed, with the publication of the legislation that will bring them into force.
The regulations specify fines starting at £100 for rule breakers, potentially rising to a maximum of £6,400 for repeat offences.
Some Tory MPs have attacked the move towards another nationwide lockdown, with one saying the government was "losing the plot".
Prof Whitty was quizzed by a select committee about the Great Barrington Declaration, which calls for "focused protection" for the elderly and other groups particularly vulnerable to Covid-19, while others continue to live relatively normally.
Prof Whitty said the arguments made by those that have signed the declaration were "scientifically weak" and "dangerously flawed".
"It would make an assumption that a very large number of people would inevitably die as a result of that decision," he told the Commons Science Committee.
"To have this as an element of policy is ethically really difficult."
Herd immunity had never been achieved in the treatment of Ebola and other new infectious diseases, argued Prof Whitty, and the kind of aggressive shielding of the vulnerable urged by the Barrington scientists would not be practically possible.
Better treatments and the prospect of a vaccine were the only hope, he told the committee, and he predicted that over the next year there will be "multiple shots on goal from science".
"We have to hold the line until that point," he added.
"Unfortunately, these economically and socially destructive tools are what we have got in the absence of anything else."
Under the lockdown beginning on Thursday, pubs, restaurants, gyms and non-essential shops would be closed across England.
The published regulations also reveal:
- There will be an exemption allowing veterans to participate in Remembrance Sunday and Armistice Day events
- People will also be allowed to visit friends or "close family members" in prison
- Visits to friends or "close family members" who are on their death bed will also be allowed
- There will be a 10pm curfew on restaurants to make takeaway deliveries
The new rules replace a tiered system of different local restrictions across England, which ministers say they want to return to after the England-wide lockdown is due to end on 2 December.
Meanwhile, at a separate parliamentary debate, a number of Conservative MPs criticised the nationwide lockdown, which faces a Commons vote on Wednesday.
One of them, Richard Drax, said the lockdowns were "destructive, divisive, and don't work".
'Losing the plot'
"They simply delay the inevitable - the re-emergence of the virus when lockdown ends, as has been shown," he said.
"Have we overreacted? Yes, I think we have. A draconian, onerous and invasive set of rules and regulations now govern our very existence."
His fellow Conservative, Bob Seeley, said lockdowns were a "dubious tool," claiming scientists were becoming "increasingly sceptical" of them as an option.
He suggested the government was "losing the plot" in the face of the spread of the virus, and there was a need for "some semblance of balance" in its response.
However with Labour supporting the new measures, they are highly likely to be approved even if there is a rebellion from Conservative backbenchers.