"Secretary Clinton was discharged from the hospital this evening," Deputy Assistant Secretary Philippe Reines said in a statement.
"Her medical team advised her that she is making good progress on all fronts, and they are confident she will make a full recovery," he said, adding that Clinton was "eager to get back to the office."
Earlier the top US diplomat, bundled up against the cold in a winter coat and wearing dark glasses, was seen in public for the first time in almost a month, when she came out of a building at the New York Presbyterian Hospital.
It was the first time the 65-year-old Clinton had been seen since catching a stomach virus on returning from a trip to Europe on December 7, which forced her to cancel a planned visit to North Africa.
Accompanied by her smiling husband, former president Bill Clinton, as well as her daughter Chelsea and several top aides, Clinton walked unaided to a waiting black van at the hospital, according to images broadcast by CNN.
Both Clinton and her family "would like to express their appreciation for the excellent care she received from the doctors, nurses and staff at New York Presbyterian Hospital Columbia University Medical Center," Reines added.
He did not say when the secretary would return to work though, promising only to issue an update in the coming days. She is due to step down after four years in office later this month, handing the baton to Senator John Kerry, who has been nominated by President Barack Obama to replace her.
Earlier, State Department spokeswoman Victoria Nuland said Clinton had been busy keeping in touch by telephone.
"She has been talking to her staff, including today. She's been quite active on the phone with all of us," Nuland told journalists.
The globe-trotting diplomat was admitted to the hospital on Sunday after a routine scan revealed the clot in a vein behind her right ear in the space between her skull and her brain.
Her doctors Lisa Bardack, from the Mount Kisco Medical Group, and Gigi El-Bayoumi, of George Washington University, said in a statement on Monday that Clinton had not suffered a stroke or any neurological damage.
They said however they would be treating Clinton with blood thinners to break up the clot, which if left untreated could be potentially dangerous.
The effects of the stomach bug caused her to become dehydrated. She then fainted and suffered a concussion, which is thought to have brought on the blood clot.
Nuland said that on Saturday, before the MRI at the hospital revealed the clot, Clinton had spoken for about 30 minutes with the UN-Arab League peace envoy to Syria, Lakhdar Brahimi.
She also spoke by phone with Qatari Foreign Minister Sheikh Hamad bin Jassim al-Thani to discuss the situation in Syria, as well as about the "need to support the Palestinian Authority" and Afghanistan.