Thursday's report, from the Work and Pensions Select Committee, reveals the deaths of at least 274 people have been investigated internally by the DWP in since April 2015.
Such inquiries - Internal Process Reviews - are launched when there is an allegation that a case has been mishandled by the DWP which has potentially contributed to serious harm or a safeguarding concern.
During the same period, 58 reviews were opened into cases where customers suffered harm - but the MPs said the scale of the failings was likely to be greater.
"That people continue to face harm after dealing with the DWP is a self-evident failure of safeguarding in the system," said committee chair Debbie Abrahams MP.
"Until recently, getting people back into work to cut costs had been prioritised over providing support and care for vulnerable people," Ms Abrahams added.
"We heard evidence that the process of engaging with the DWP... too often led to mental distress.
"Deep-rooted cultural change of the DWP is desperately needed to rebuild trust and put safeguarding at the heart of policy development.
"Introducing a statutory duty to safeguard vulnerable claimants for the department is a fundamental part of this."
A new law, holding the secretary of state accountable for safeguarding clients, would ensure that everyone saw it as their responsibility to protect claimants, says the committee.