From Ghana, Trump will travel to Malawi, then Kenya, and finally to Egypt, an itinerary that places the typically private first lady half a world away from her headline-dominating husband - and into the global spotlight. She was welcomed at the airport with dancing and drumming, schoolchildren waving mini US and Ghanaian flags and the gift of a flower bouquet.
Trump's plane touched down in Ghana's capital of Accra early Tuesday.
She is scheduled to visit a hospital in Accra to learn about newborn health and also have tea with Mrs Akufo-Addo at the presidential residence, Jubilee House.
The U.S. First Lady is also involved in various charities, including Martha Graham Dance Company, the Boys Club of NY, the American Red Cross, Make a Wish Foundation and the Police Athletic League.
Ahead of her trip, Melania said she was looking forward to visiting "four attractive and very different countries in Africa".
Trump is due to visit a hospital in Accra.
Some think her mission is created to soften relations with the continent after President Trump reportedly referred to several African nations as "s***hole countries" 10 months ago. She is in Ghana to advance the cause of her "BE BEST" campaign targeted at empowering children.
Others said they knew about Trump's visit but did not know what she would be doing. Would she offend a whole nation with one pair of shoes? anything was possible - but we didn't expect her to kick off her trip by weighing in on one of fashion's most heated conversations.
Melania Trump has departed Washington for a four-country tour of Africa. It also portrays Trump as a first lady who is passionate about serious issues. She added: "Let's face it-most children are more aware of the benefits and pitfalls of social media than some adults".