Breaking with tradition, Clinton's inaugural journey will take her to Japan, Indonesia, South Korea and China rather than the United States' historic allies in Europe and the perennial trouble spots of the Middle East.
Clinton leaves Washington on Sunday and plans to spend two nights in Tokyo, one each in Jakarta and Seoul, and then two in Beijing before returning to Washington on February 22.
While US President Barack Obama has not detailed his Asia policies, analysts said the visit itself was a powerful signal he wants to keep his campaign promise to consult allies such as Japan and South Korea after their perceived neglect by former President George W Bush.
Clinton also hopes to lay the ground to work with China to curb the nuclear ambitions of North Korea and Iran and to cope with the global financial crisis and climate change – priorities that may mute any critique of the Chinese human rights record, which she famously criticised in a 1995 speech in Beijing.
"This, in many ways, should be a listening tour," said Elizabeth Economy, director for Asia studies at the Council on Foreign relations.
"We need to hear from the Chinese what ... their priorities are in the relationship with the United States because ... that is how we are going to get any leverage," she added.
LONG LAUNDRY LIST
Analysts advised Clinton not to confront the Chinese with a series of demands on her first visit as secretary of state.
That said, the laundry list is long.
The United States would like China to do more to support internal consumer demand and reduce its reliance on exports to generate its growth. It would also like to see the Chinese currency appreciate, making US exports more competitive and helping to narrow the vast US trade deficit with China.
In announcing her trip, the State Department put "financial markets turmoil" as the first item on her Asia agenda on a list that included humanitarian issues, security and climate change but omitted North Korea – a key issue in Tokyo and Seoul.
In recent months, the North has repeatedly warned of war and threatened to destroy the conservative government in Seoul that has ended a decade of free-flowing aid to Pyongyang after taking office a year ago.
There are also reports Pyongyang may be preparing to test its longest-range Taepodong-2 missile, designed to hit Alaska.
Talks to end North Korea's nuclear arms program have been stalled for months with Pyongyang complaining that aid given in return for crippling its nuclear plant at Yongbyon is not being delivered as promised in a "six-party" deal it struck with China, Japan, Russia, South Korea and the United States.
The secretive North has balked at a demand by the other powers that it commit to a system to check claims it made about its nuclear program, leaving the talks in limbo.
While Clinton has said she is committed to the talks, and is expected to name retired diplomat Stephen Bosworth to lead the US delegation, there remains lingering anxiety in both Seoul and Tokyo that the Obama administration could cut them out should it pursue closer bilateral talks with North Korea.
There are also fears the United States could accept a nuclear North Korea, a possibility analysts dismissed.
"In Tokyo, she will reassure them of the primacy of the US-Japan alliance ... and in South Korea, she will remind them that Obama's commitment to talk with adversaries doesn't mean that we are going to allow North Korea to play Washington off against Seoul," said a US congressional aide.
SUBTLE ON HUMAN RIGHTS
Spliced between her stops in Japan and South Korea, Clinton plans to spend a night in Indonesia, the world's most populous Muslim country where Obama lived during part of his childhood.
The visit appeared in sync with Obama's desire to forge a better US relationship with the Muslim world, where many of Bush's policies, including the 2003 US-led invasion of Iraq, were deeply unpopular.
Clinton ends her trip in Beijing, which an aide said she last visited when her husband, former President Bill Clinton, was in the White House.
As US first lady in 1995, Clinton critiqued Chinese policy at a UN conference in Beijing without citing China by name.
"Freedom means the right of people to assemble, organize, and debate openly. It means respecting the views of those who may disagree with the views of their governments," she said.
"It means not taking citizens away from their loved ones and jailing them, mistreating them, or denying them their freedom or dignity because of the peaceful expression of their ideas and opinions."
Human rights groups including Amnesty International, Freedom House and the International Campaign for Tibet urged Clinton to speak out about suspected torture in police custody, censorship and abuses of human rights defenders.
But analysts said Clinton could not afford to jeopardize Chinese cooperation on North Korea and other issues.
"She is quite capable, in a diplomatic and subtle way, of bringing the issue up so that she has put a marker down without throwing it in their face," said Jack Pritchard of the Korea Economic Institute, a former White House Asia specialist.