The union claimed 24 of 30 sites will shut at the service, which employs 1,500 frontline nursing and professional staff.
NHS Direct hit back, saying that so far it has only made clear which sites will be kept open to deliver the new NHS 111 service and had not said what will happen to the others.
But Sandra Maxwell, Unison's convenor at NHS Direct, said: "Hundreds of dedicated nursing and NHS professionals are to be made redundant at a huge cost, when their skills could be used within the new NHS 111 service if only the Department of Health took some decisive action."
National officer Michael Walker added: "The Secretary of State for Health should step in and stop this disaster immediately. We need action and we need it now.
"Axing dedicated hard-working nurses is never a good idea at any time, but this will directly impact on patient care. There is no doubt that patients will suffer as a result of this move."
A Unison spokesman added: "Given that many of these NHS call centres are in areas of high unemployment there are very real fears for the staff's future job prospects.
"The Government spending millions on making nurses and NHS professionals redundant at a time when the NHS is under great strain is truly scandalous."
NHS Direct has been bidding for contracts across England to provide the NHS 111 service, which is for patients who need medical help but are not emergencies.
It has been awarded contracts to run the service for 34% of the population, and will deliver it from six of its existing call centres.
Centres where a decision has yet to be made will stay open until June 2013 unless the landlord has served notice or all staff have already been transferred elsewhere.
NHS Direct chief executive Nick Chapman said: "We have not confirmed that any sites are closing.
"At this stage we have confirmed which sites we will be keeping open to deliver NHS 111 in the areas where we have been commissioned to provide the service.
"The future of other NHS Direct sites has not been decided. We are waiting for decisions from the Department of Health and the NHS Commissioning Board about the future of other non-111 services that we could be asked to deliver before making decisions."
NHS Direct answers 4.2 million calls for health advice and information for patients in England every year.