Al-Kharafi worked in Kuwait University's Department of Chemistry from 1975 to 1981. In 1984 she became chair of the department and served as Dean of the Faculty of Science from 1986 to 1989. She became a professor of chemistry at Kuwait University in 1987. On 5 July 1993, Emir Jaber Al-Ahmad Al-Jaber Al-Sabah issued a decree appointing Al-Kharafi as rector of the university, and she became the first woman to head a major university in the Middle East. Al-Kharafi helped reconstruct Kuwait University after the First Gulf War, which ended in 1991. She served as president from 1993 to 2002 where she oversaw 1,500 staff members, over 5,000 employees, and over 20,000 students.
Al- Kharafi has demonstrated to be an advocate for research in Kuwait. In 1986, Al- Kharafi and her colleagues explored and compared the rich development of Kuwaiti scientific research in comparison to other nations in the third world. In her publication, Al- Kharafi was able to demonstrate the ability of Kuwait's higher education institutions to engage in relevant scientific research.
Al-Kharafi has studied the impact of corrosion on engine cooling systems, distillation units for crude oil, high temperature geothermal brines, and tap water. She has also studied corrosion in polluted water and metal corrosion caused by pollution. As an electrochemist, she studied the electrochemical behavior of metals and metal alloys including aluminum, copper, platinum, niobium, vanadium, cadmium, brass, cobalt, and low carbon steel. She collaborated on the discovery of a class of molybdenum-based catalysts that improve gasoline octane without benzene by-products.
She joined the Board of the United Nations University in 1998. Following the passage of women's suffrage in Kuwait in 2005, she said "when we have political rights, we can express our opinion and vote for the correct person... This gives us the chance to express our ideas." In 2006, she helped found the American Bilingual School in Kuwait. She is the vice president of The World Academy of Sciences. She serves on many boards, including the Kuwait Foundation for the Advancement Sciences, Alqabas, the Kuwait-MIT Center for Natural Resources and the Environment.