Mendelsohn was born in Melbourne, Victoria, the son of Carole Ann (née Ferguson) and Frederick Arthur Oscar Mendelsohn. His father is a prominent medical researcher who previously headed the Howard Florey Institute in Melbourne, where he maintains the status of Professor Emeritus. Ben and his two brothers, Tom and David, as well as his mother (deceased), a registered nurse, lived in Europe and the US for long periods of time, and returned to Melbourne when he was in high school. He attended Heidelberg Primary School and Eltham High and Banyule High schools. He took drama because he thought it was an easy class. Mendelsohn was the only one of his friends to follow up with an audition for Crawford Productions that was being advertised.