The size of the moves in the currency markets are order-of-magnitude larger than the stock market's," said Art Hogan, chief market strategist at Wunderlich Securities.
The news raised concerns that other countries might leave the union and that global growth would come under significant pressure, while the actual timeframe of the U.K.
The Dow Jones industrial average closed down 260.51 points, or 1.50 percent, at 17,140.24, with American Express the greatest decliner and Verizon and Johnson & Johnson the only advancers.
The S&P 500 closed down 36.87 points, or 1.81 percent, at 2,000.54 with materials leading eight sectors lower and telecoms and utilities the only advancers.
The Nasdaq composite closed down 113.54 points, or 2.41 percent, at 4,594.44.