In a statement just before his departure, Netanyahu called the first visit by an Israeli premier to the region in decades "historic". He is expected to land in Uganda around 1:00 pm (1000 GMT.)
The trip comes at a time when Israel is launching a $13-million aid package to strengthen economic ties and cooperation with African countries, said Netanyahu's office.
Israel would also provide African states with training in "domestic security" and health, it said.
"Coming on a journey like this is also very important from diplomatic, economic and security perspectives and I am pleased that Israel is going back to Africa in a big way," Netanyahu said in a statement, adding: "We are opening Africa to Israel again."
The Arab-Israeli conflict drove a wedge between African countries and the Jewish state in the 1960s.
Following wars between Israel and its neighbours in 1967 and 1973, North African nations led by Egypt put pressure on sub-Saharan African states to cut ties with Israel, which many did.
In an interview with Uganda's Daily Monitor newspaper ahead of his visit, Netanyahu said his visit was an attempt to thaw relations.
"I'm very open about it, that's true," Netanyahu said, according to the paper.
Beyond diplomacy and trade, the trip will have deep personal meaning for Netanyahu.
His brother Yonatan was killed in July 1976 as he led a commando raid in Entebbe, Uganda, to free passengers aboard an Air France plane hijacked by two Palestinians and two Germans.
Uganda's deputy foreign minister Henry Okello Oryem told AFP Netanyahu would be given a 19-gun salute on arrival, before "proceeding to the 40th anniversary commemoration ceremony at the old airport terminal."
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