She has accompanied President Donald Trump on foreign visits, but she chose Africa for her first multi-nation trip alone.
The visit is being organised in partnership with USAID and will involve Ghana and three other countries, which she has described as "four attractive and very different countries in Africa".
Trump has focused on children as her signature issue and plans to promote child wellbeing during her four-country tour.
The first lady chose Africa as her destination as it had always been on her wish list of places to go, according the White House.
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The trip, which reportedly will focus on health care and education, falls in line with the first lady's domestic goals, identified in her Be Best initiative.
Ghana's first lady, Rebecca Akufo-Addo, welcomed her at the airport in Accra.
Mrs Melania Trump also donated a photo therapy machine to the hospital, which will be used to treat jaundice.
Shortly after her arrival, Trump visited the Greater Accra Hospital. She toured wings of the hospital and distributed gifts of teddy bears wrapped in baby blankets.
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She has typically stayed out of the spotlight since her husband became president yet she has made headlines for rare public appearances. "I don't think I have ever heard her name, Melania".
In return, Melania Trump received a kente cloth, a Ghanaian fabric distinguished by its multicolored strips of cotton or silk, and an artifact.
"Why are we having all these people from shithole countries come here?" the president reportedly said, apparently also asking why more "people from countries like Norway" don't come to the USA instead.
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