Health Secretary Jeremy Hunt has warned NHS bosses against allowing a culture that is "legalistic and defensive" in dealing with staff who raise concerns over patient care.
In a letter to all English NHS trusts, Mr Hunt highlighted fears that "gagging" clauses were being used to "frustrate" such whistleblowing.
A climate of "openness and transparency" is essential, he said.
It comes after one former NHS trust boss broke a gag to talk to the BBC.
Gary Walker, former chief executive of United Lincolnshire Hospitals Trust (ULHT), said he had been forced out of his job and gagged from speaking out about his concerns over patient safety.
'Positive move'Andrew Hosken BBC Today programme
The row over secret gagging clauses has focused attention on the man at the top of the English NHS, Sir David Nicholson.
His position was already being questioned in the wake of a highly critical report on the Mid Staffordshire Hospitals scandal, where hundreds of patients may have died from neglect and abuse.
However Sir David escaped personal censure from inquiry chairman, Robert Francis QC.
Following the report, another 14 NHS trusts have been placed under investigation.
What makes the gagging row potentially so toxic for Sir David is one of those trusts, the United Lincolnshire Hospitals Trust, has been trying to enforce Gary Walker's gagging clauses with the threat of legal action.
Since Mr Walker broke cover, more people are asking whether Sir David and other senior NHS civil servants can bring about the cultural change and openness Jeremy Hunt and many others consider essential.
In his letter, Mr Hunt called for the NHS to "recognise and celebrate" staff who had "the courage and professional integrity to raise concerns over care".
The health secretary insisted that "fostering a culture of openness and transparency" was essential in creating a climate "where it is easy for staff, present and former, to come forward with any concerns they have relating to patient safety".
Mr Hunt also warned NHS bosses against the "institutional self-defence that prevents honest acknowledgement of failure".
"I would ask you to pay very serious heed to the warning from Mid Staffordshire that a culture which is legalistic and defensive in responding to reasonable challenges and concerns can all too easily permit the persistence of poor and unacceptable care," he said.
Mr Walker, who was sacked in 2010 for gross professional misconduct for allegedly swearing in a meeting, told the BBC he had no choice but to sign an agreement linked to a confidentiality clause in April 2011.
He said he was gagged by the NHS from speaking out about his dismissal and his concerns over the quality of care at the trust.
After breaking the order, lawyers for the trust then warned him he would have to repay £500,000.
Speaking to BBC Radio 4's Today programme on Saturday, Mr Walker applauded Mr Hunt for "clearly taking a personal interest" in his case and the issue of gagging orders.
"I think that's a very positive move."
"I don't think it's simply about the Lincolnshire Trust," he added, calling for Mr Hunt to investigate the "chain of command" that led to the gagging, which he said included the Department of Health, the East Midlands Strategic Health Authority (SHA) and the Lincolnshire Trust.
"I don't think Mr Hunt can investigate his own department so I think he should be looking for someone exceptionally independent from all of this."
Test caseBBC Radio 4 Today programme reporter Andy Hosken said Mr Hunt's letter could spell the end of the National Health Service gag if the NHS trusts' chairmen to whom he wrote actually followed the advice and guidance contained within the letter.
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Our correspondent said the letter was certainly a warning shot across the boughs of the trusts. It appeared the use of these gagging clauses was widespread in the NHS, he added.
A spokesman for the SHA said it had always acted "appropriately and properly" in the "interest of patients".
And ULHT has said the allegations that they had tried to stifle debate about patient safety issues were "incorrect".
ULHT is one of 14 trusts in England currently being investigated for high death rates, in the wake of the Stafford hospital scandal, where hundreds are believed to have died after receiving poor care.
It emerged on Friday that police and prosecutors are now studying a damning report into failures at Stafford to see whether any criminal charges should be brought against staff.
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