East London-born Lana Marks was nominated for the post by President Donald Trump.
Marks, whose parents immigrated to South Africa from Lithuania in the 1930s to escape anti-Semitism, is from Palm Beach, Florida.
Her appointment was confirmed by the US Senate in September.
News24 reported on Saturday that the ambassador posted an image of herself on board a Delta Airlines flight with the caption: ‘And, we’re on our way! We can’t wait to arrive in South Africa and begin our new journey together!’
Having grown up in South Africa, Marks emigrated after her 1976 marriage to psychiatrist Neville Marks, first to Bermuda, then to the United States.
Marks, who can reportedly speak both Xhosa and Afrikaans, is best known ‘for an empire built on designer handbags’, according to News24. The business has stores in Palm Beach, New York, Beverly Hills and Dubai.
It is reported that, besides focusing on the ‘safety and security’ of all Americans in South Africa, Marks intends giving attention to trade relations, HIV/Aids and women and youth empowerment.