Conservative MPs have set up a group to fight any future lockdown in England, arguing it would be "devastating" for the economy and "cost lives".
The Covid Recovery Group, which has around 50 MP members, wants the country to "live with" coronavirus after nationwide restrictions end next month.
The "cure" prescribed by the government ran "the risk of being worse than the disease", MP Mark Harper said.
But the PM has stressed the NHS faces a "medical disaster" without action.
A further 20,412 coronavirus cases were reported in the UK on Tuesday, with another 532 deaths within 28 days of a positive test recorded.
The four-week lockdown in England - which includes the closure of pubs, restaurants and non-essential retail, while curbing household mixing and unnecessary travel - is scheduled to end on 2 December.
Parliament overwhelmingly backed the restrictions earlier this month, but 34 Conservative MPs, concerned about civil liberties and the effect on wider health and the economy, rebelled against the government.
Another 19, including former Prime Minister Theresa May, abstained.
The government says it wants a return to regionalised, tiered restrictions when lockdown ends - and ministers have been warned of an even larger rebellion if they try to extend it into Christmas and the New Year.
The Covid Recovery Group - which includes ex-Chief Whip Mr Harper and the chairman of the 1922 committee of backbench Conservative MPs, Sir Graham Brady - says the "devastating cycle" of prohibitions cannot go on.
It wants ministers to investigate whether restrictions are costing more lives than they are saving, by stopping cancer and dementia treatments and increasing suicide rates among the under-40s.
The group is calling for the "monopoly" it says scientists have on advising the government to end, and an assurance that no policies will go before Parliament without three "independent" experts backing them first.
Figures published on Tuesday showed redundancies rose to a record high of 314,000 in the three months to the end of September, as firms laid off people in anticipation of furlough ending in November.
Despite the government extending the wage-subsidy scheme to March, economists say the jobs picture remains bleak.
Mr Harper said the country needed to find a "sustainable way" of living with Covid until a vaccine was available for mass use to stop "immense" economic damage.
"Lockdowns cost lives, whether in undiagnosed cancer treatments, deteriorating mental health, and missed A&E appointments - not to mention the impact it has on young people's education, job prospects and our soaring debts," he said.
"The cure we're prescribing runs the risk of being worse than the disease."
The new group, he added, would "play its part in helping the government to deliver an enduring strategy for living with the virus... command public support, end this devastating cycle of repeated restrictions".
Health Secretary Matt Hancock said it was critical people continued to follow the rules to get the infection rate down, adding that "our plan is working".
He added that the NHS would be ready to begin the roll-out of a new vaccine from next month, if it gets approval.
But Prime Minister Boris Johnson has warned people not to "rely" on this "as a solution" to the medical emergency caused by coronavirus.