In 1929, Merrill anticipated that the stock market would crash, prompting him to divest most of his holdings before the Great Depression took hold. Eventually, he also merged his wire and retail brokerage operations with E.A. Pierce and Co., pushing Merrill Lynch & Company into restructuring and focusing on investment banking.
After his death, Merrill's estate supported the Charles E. Merrill Trust which in turn funds the Merrill Science Center at the University of California. In 1976, Merrill was also inducted into the Junior Achievement US Business Hall of Fame.