Up to half a million disabled people and their families stand to lose out under the government's proposed Universal Credit, a report says.
The Children's Society, Citizens Advice and Disability Rights UK say 100,000 households with children could have incomes reduced by up to £28 a week.
They are urging a rethink, particularly on help for future claimants.
But David Cameron said greater support was being targeted at the most disabled and overall funding was going up.
The Universal Credit will replace Jobseeker's allowance, tax credits, income support, employment and support allowance - formerly known as incapacity benefit - and housing benefits with a single payment.
The system will be "piloted" in parts of north-east England next April and will come into force across Britain for new claimants from October 2013.
Existing claimants will be transferred to the new system in stages until 2017, while Universal Credit will be capped at £26,000 per household.
The report argues that the changes will mean 230,000 severely disabled people who do not have another adult to assist them will receive between £28 and £58 less in benefits every week.
It also states that around 116,000 disabled people who work will be at risk of losing around £40 per week.
The report says the impact of the cuts in support for disabled children could be "extremely severe" for families currently receiving the mid-rate "care component" of the Disability Living Allowance, a payment made where a child can be severely disabled but does not need care overnight.
Of those families affected, one in 10 expressed fears that they could no longer afford their own home, while two thirds said they would have to cut back on food, and more than a half said it would lead them into debt.
Some families said the changes to support for disabled children could result in their children having to be placed in full-time residential care.
The report says 83% of those eligible for the severe disability premium, which will be abolished under the changes, reported that a reduction in benefit levels would mean they would have to cut back on food and 80% said they would have to cut the amount they spent on heating.
The changes start to come into force from October next year and current benefit claimants who move on to Universal Credit will not see an immediate reduction in their payments.
But they will have their level of benefit frozen, with no increases to take into account rising prices, campaigners say, and they may see their support cut immediately if their household circumstances change.
Independent peer Baroness Tanni Grey-Thompson, who shares the title of Great Britain's most successful female Paralympian with cyclist Sarah Storey, said the findings of the report did not make "easy reading".
She told the BBC: "Under the new system it is going to be difficult for a number of disabled people. The government say people are protected but it's only for current benefit claimants.
"What we want to do is ask the government to think again. We are in a situation where the regulations of the Welfare Reform Bill are coming to us quite soon and we can make changes. I think we can improve the system to help disabled people lead better lives."
But, asked about the issue at prime minister's questions, Mr Cameron defended changes to disability benefits, saying overall funding would increase from £1.35bn in 2011 to £1.45bn in 2015.
"Under the plans, no recipients will lose out unless their circumstances change and all current recipients are fully cash-protected by a transitional scheme," he told MPs.
"What we are doing, and this is a decision and a choice we have made, is for future recipients we are going to increase the amount we give to the most severely disabled children and there will be a new lower amount for less disabled people.
"That is a choice we are making. Increasing the overall amount of money, focusing on the most disabled - that I think shows the right values and the right approach."
The report summarises the findings from three research reports based on evidence from surveys of almost 3,500 disabled people and their families, as well as a parliamentary evidence session.