The donation is for a permanent endowment to support need-based financial aid for undergraduate students from the United States and other countries.
Duke University President Richard H. Brodhead said it was largest donation made by individuals to support financial aid in the university's history.
The gift includes $30 million for U.S. students and $20 million for international students.
Including Monday's new contribution, the Karshes have given $85 million for undergraduate financial aid at Duke.
More than half of Duke's undergraduates receive some form of financial assistance from the university.
Bruce Karsh is President of Oaktree Capital Management, a global investment management company he co-founded in Los Angeles in 1995. He chairs the Board of Directors of DUMAC, LLC, which manages Duke's endowment.
Martha Karsh is an attorney and co-founder of Clark & Karsh, an architecture, design and development firm in Los Angeles. A graduate of the University of Virginia and Virginia Law School, she is a trustee of the Virginia Law School Foundation and a member of the Advisory Board for KIPP LA Schools.