Raphael Mechoulam was born in Sofia, Bulgaria in 1930. His father was a physician and head of the Jewish hospital in Sofia.  Raphael Mechoulam went to an American Grade School in Sofia for 4 years until it was closed by the pro-German government.
From 1942, for over 2 years – during the 2nd world war - his family lived in small villages in the Balkans. His parents believed that the family is safer there.
Nevertheless his father was taken to a concentration camp for part of this time. 

Raphael Mechoulam immigrated to Israel in 1949. He studied biochemistry at the Hebrew University in Jerusalem (M.Sc.) and the Weizmann Institute in Rehovot (Ph.D.) He spent a year in New York, at the Rockefeller Institute and returned to the Weizmann Institute in 1960. He worked on the chemistry of various natural products. He initiated his work on hashish, which he received from the Police. In 1966 he moved to the Hebrew University, where he became a full professor in 1972. From 1979 to 1982 he was Rector (Academic Head) of the Hebrew University. He retired in 2000 but continued his research. He still has a lab with 3-4 post-doctoral researchers. His work has been mostly on the chemistry of natural products, the best known being on cannabinoids. In collaboration with numerous colleagues in Israel and abroad he has also published in pharmacology and on clinical trials.
He has published about 480 scientific papers and has received numerous national and international prizes, including the Israel Prize – the most prestigious Israeli Prize – as well as a prize from the US National Institutes of Health. He is a member of the Israel Academy of Sciences, where he headed the Natural Sciences section from 2007 to 2013.

He married Dalia (born Borovitch) in 1955 and they have 3 children, Roy, a professor of mathematics at the Technion in Haifa, Hadas, an M.D. ophthalmologist and Dafna, an M.D. paediatric neurologist. He has 7 grandchildren.