Hillary Clinton’s head spokesman PJ Crowley resigned on Sunday after criticising the US government’s treatment of the former soldier accused of leaking secret cables to Wikileaks.
Crowley had angered the White House after accusing the Defense Department officials holding Bradley Manning of being "ridiculous and counterproductive and stupid".
His comments, which he made to small academic audience, were in relation to claims that Manning is being tortured while in solitary confinement at the Quantico military base, in Virginia.
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In a statement on Sunday Crowley said: "Given the impact of my remarks, for which I take full responsibility, I have submitted my resignation."
It is understood he will stand down immediately.
Clinton, the US secretary of state, said she accepted Crowley's resignation "with regret".
She added that he had served his nation "with distinction", "motivated by a deep devotion to public policy and public diplomacy".
Manning is awaiting trial on charges that he leaked confidential US government files, including a tranche of diplomatic cables, which were later published through the Wikileaks website.
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His lawyers claim he is being kept in a windowless cell for 23 hours a day and forced to sleep nude.
Amnesty International have denounced his conditions as of Bradley Manning's detention as "unnecessarily harsh”, "punitive" and “inhumane”.
Crowley was speaking at Massachusetts Institute of Technology when a member of the audience asked him about Manning, referring to it as the “elephant in room” and the “torturing of a prisoner in military prison”.
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He said: "What is being done to Bradley Manning is ridiculous and counterproductive and stupid on the part of the department of defence."
Last week US president Barack Obama insisted that Manning was not being mistreated.
The president revealed that he had asked Pentagon officials "whether or not the procedures that have been taken in terms of [Manning's] confinement are appropriate and are meeting our basic standards."
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Obama added that Pentagon officials "assure me that they are. I can't go into details about some of their concerns, but some of this has to do with Private Manning's safety as well."
Left-wing commentators in America hit out what they see as Crowley’s forced departure.
Liberal blogger Matt Yglesias posted on Twitter on Sunday: "Sad statement about America that PJ Crowley is the one being forced to resign over Bradley Manning.”