The 11-day trip -- Clinton's longest since becoming the top US diplomat six months ago -- will highlight issues close to her heart including women's rights with plans to meet rape survivors and female entrepreneurs.
Clinton will seek to build ties with three African powers -- Kenya, Nigeria and South Africa -- and visit three nations recovering from conflict -- Angola, Democratic Republic of Congo and Liberia. She will end with a stop in small US ally
Current hotspots will also be high on her agenda. She plans to seek pressure on Eritrea, which is accused of funding Islamic militants in troubled neighbor Somalia, and push for greater democracy in Zimbabwe.
"The administration is committed to Africa. The administration is capable of handling multiple foreign policy issues at one time," Johnnie Carson, the assistant secretary of state for Africa, told reporters.
He rejected suggestions that the United States was worried about the growing influence of China, which has ramped up ties with Africa but puts little emphasis on democracy and human rights.
"The mention of our colleagues from Asia is a Cold War paradigm, not a reflection of where we are today," Carson said.
Clinton kicks off her visit Wednesday in Kenya, the birthplace of the father of President Barack Obama whose African roots have spurred intense interest on the continent in his administration.
Obama chose Ghana, not Kenya, for his first trip to the continent last month. He delivered a speech urging Africans to take charge of their future by demanding better governments and fighting corruption.
The State Department has highlighted that this will mark the earliest into a US administration that both a president and secretary of state have visited Africa.
Jendayi Frazer, assistant secretary of state for Africa until January under president George W. Bush, called it a "silly" factoid and noted that former secretary of state Colin Powell went to Africa four months into his term.
Obama's trip to Ghana "was more symbolic than substantive. He stayed there less than 24 hours and made a speech to Africans that some considered a bit patronizing," Frazer told AFP.
Frazer, now a professor at Carnegie Mellon University, said there has been a "huge vacuum" in Africa policy since Obama took office.
She praised Clinton for her extensive itinerary in Africa but said it was important for her to bring concrete initiatives.
"The question is what meat will they put on the bones, what substance will they bring," Frazer said.
In Nairobi, Clinton will highlight what the administration sees as a key achievement so far for Africa -- a 20 billion-dollar fund to boost agriculture and ease hunger in poor nations. Obama and other leaders of the Group of Eight rich nations sealed the fund last month in Italy.
But the Nairobi stop could also be one of the most tense.
Clinton will address a forum of some 40 nations covered by the African Growth and Opportunity Act, a US law giving market access to sub-Saharan nations committed to democracy and free markets.
Some African nations have voiced concern over moves in the US Congress to extend trade preferences to other poor countries such as Bangladesh and Cambodia.
US Trade Representative Ron Kirk, who will accompany Clinton to Kenya and then visit Ethiopia and Senegal, said he would retort that African nations needed to invest in their people and infrastructure to compete.
"I think some of what we may respond with is a little bit of tough love," Kirk told reporters.
Aides said it would be Clinton's first visit to all the countries except South Africa and that her husband, former president and champion of African development Bill Clinton, would not accompany her.
As has become her hallmark, Clinton will spend much of her time outside of the corridors of power, mingling with students and touring clinics handling Africa's AIDS crisis.
One trip highlight will be a visit to Goma, the town in the eastern Democratic Republic of Congo flooded with refugees since the 1994 genocide in neighboring Rwanda.
Clinton will meet with survivors of soaring sexual violence in the area, where the United Nations says nearly 3,500 women have been raped since the start of the year.