The letter, spearheaded by the Christian think tank Ekklesia, expresses concern about over Iain Duncan Smith's welfare changes, including:
* sanctioning benefit claimants when they miss jobcentre appointments;
* a benefits cap of £26,000;
* halving children's disability payments, and;
* work assessments which are ruling sick and disabled people are fit to work.
The letter also refers to Iain Duncan Smith's Christian faith, which he has spoken of in the past.
Virginia Moffatt, the Chief Operating Officer of Ekklesia, told Premier: "I think it's terrible. It's worse than I've ever known it in my life, and it's about to get a whole lot worse with next week's budget, and where yesterday it was being mooted that Employment Support Allowance, which is an allowance for disabled people, could be cut by thirty pounds a week.
"That will have a significant and awful impact for people who are sick and disabled.
Citing a case study of the effects have on people, she said: "Paul Leaky, for example, was a man in Scotland who actually left his letters about his [fitness to work] assessments on the desk before he committed suicide. So there's definitely evidence linking these assessments to ill-health and people dying.
"The welfare state that we had in this country, that is currently being dismantled, was actually founded through Christian thinking. So many of the original thinkers...who contributed to the Beveridge Report which contributed to the welfare state were Christians themselves.
"He [Iain Duncan Smith] has made no bones about the fact he is a committed Catholic and we are committed Catholics too. We all share faith, we all share the same desire to make life better for people who are poor.
"But what we're saying to him is, with all due respect and wishing to have dialogue, is that... [his] approach isn't working."
The current welfare budget is approximately £220bn - the largest department of public expenditure. Health spending is second, at approximately £110bn.
Just under half of the welfare budget goes to state-issued pensions and other age-related benefits such as winter fuel allowance, free TV licenses and bus passes.
The large proportion going to pensions is linked to a population which is living longer.
A Department for Work and Pensions spokesman said: "The benefits system we inherited in 2010 was broken, frequently trapping the very people it was meant to help in a state of welfare dependency.
"Our reforms are restoring fairness to the system – for claimants as well as the taxpayer.
"We have maintained a valuable safety net for those that need it, while also ensuring that people who can work are given the skills and opportunities to get a job."
Listen to Premier's Aaron James speaking to Virginia Moffatt here:
You can read Ekklesia's open letter here.