Prior to her tenure as First Lady, H.E Rebecca Naa Okaikor Akufo-Addo worked with the Merchant Bank and served as a legal secretary for multinational law firms, including Clifford Chance/Ashurst Morris Crisp, in the United Kingdom. 

In her capacity as First Lady, Madam  Akufo-Addo has made significant contributions to the lives of Ghanaian women and children.  Through local, regional and international partnerships, she has been actively involved in projects that focuses on health care, providing support for inclusive learning for children with special needs, ensuring access to urgent medical intervention, literacy and entrepreneurship trainings which are accredited to the Rebecca Akufo-Addo Foundation (Rebecca Foundation) established in 2017. Since its inception, the foundation has made significant impact through its Learn to Read, Read to Learn, Free to Shine projects as well as the commissioning of the Paediatric and Intensive care unit at the Komfo Anokye Teaching Hospital in Ghana. She is a patron of the Infanta Malaria, a charity organization dedicated to the prevention of Malaria in children.