On the fifth leg of a tour that has already taken her to troubled South Sudan and focused on the continent's security woes, Clinton chose to emphasise women's rights and education.
The first US chief diplomat to visit the southern African nation stopped at the Lilongwe Girls Secondary School in the capital after meeting with President Joyce Banda.
The diplomat was visibly moved when a girl wrapped a colourful gift around her -- an orange, blue and grey traditional African fabric locally known as chitenge.
Dozens of other girls welcomed Clinton with singing.
She then took time to shake hands with every woman at the school, where US volunteer group Peace Corps is holding a week-long camp for girls from across the country.
Clinton shared her mother's story as encouragement to the girls in a country where women's rights have been an upward battle, an issue which lay close to her heart.
"She overcame a sea of difficulties early in her life. She was abandoned by her parents and grandparents, abused and neglected," Clinton told her eager audience.
"You have the right to make your own choices about your future. So aim high, stand tall and be proud to be a woman in this time and in this country with so much promise," she said.
She looked forward to see young women leaders alongside young men on her next trip to Malawi, she said.
Clinton earlier on Sunday met with Banda, Africa's second woman leader after Liberia's Ellen Johnson Sirleaf, at her official residence State House where the two exchanged warm words.
"For a long time, we have been women and children activists. I have been waiting for the day when we would meet," Banda told Clinton as the two held hands.
She "encouraged President Banda to be a role model in Southern Africa for more democratic governance and also regional integration among the states of this region," said a State Department official who attended the meeting.
Clinton "commended the decisions of Banda's first 100 days" including a move to float the currency.
Malawi devalued the kwacha by nearly 34 percent against the US dollar in May, after it traded at double the official exchange on the black market and drove foreign currency from the banking system.
Clinton also warned the Malawi government against corruption, which she called a "hidden tax on the Malawi people".
During her last stop in the country at a milk cooperative she announced a $46 million (37 million euros) investment in agriculture over the next three years.
Milk production had increased by 500 percent over the last decade thanks to funds from the US, the impoverished nation's largest bilateral donor, she added.
As part of a marathon eleven-day Africa tour she flew later Sunday to South Africa, where she would meet with anti-apartheid icon and Nobel Peace Prize Laureate Nelson Mandela in the week.
A spokeswoman confirmed Clinton tagged visits to Nigeria and Benin onto the trip after South Africa. She is also expected in Ghana for the state funeral of late president John Atta Mills.
Banda, a former womens' right activits, was sworn in as president in April following the death of late president Bingu wa Mutharika.
Her rise to power was a victory in a nation where a gang stripped women in public in January for wearing trousers.
Banda swiftly set about restoring relations with foreign donors, who had suspended funds due to concerns about hardline governance and rights issues under Mutharika.
Her sister Anjimile Oponyo was hired by Madonna to run a school for girls the US pop star set up in Malawi, although that project collapsed and she was sacked.
In June the US said it would restore aid worth $350 million to Malawi's energy sector in light of Banda's "bold actions" to reform the government.
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