Lewisohn was born in Berlin, Germany, and immigrated to the United States in 1890 with his parents. The family settled in Charleston, South Carolina. Though his mother was the daughter of a rabbi, the family converted to Christianity. In his youth, Lewisohn was an active Methodist. After graduating with honors from the College of Charleston, he went to Columbia University in 1902 to work on a doctorate. He received the degree of A.M. in 1903. In 1904 he was told by his advisers that a Jew would never be hired to teach English literature at an American university. The bitter irony in this advice led Lewisohn to return to Judaism and he became an outspoken critic of American Jewish assimilation. In 1948 Lewisohn was among the founding faculty members of Brandeis University, where he taught until his death.

It was Lewisohn who first translated Franz Werfel's The Song of Bernadette into English.

Lewisohn died in 1955, at the age of 73, in Miami Beach, Florida.