Analysts said markets were jittery ahead of Tuesday's election as polls continued to show Hillary Clinton's lead over Donald Trump was narrowing in the final days of the race.
The Dow Jones finished 77 points or 0.4% lower on 17,959.64, while the wider S&P 500 dropped 0.7% to 2,097.94.
The tech-heavy Nasdaq fell 48 points, or 0.9%, to 5,105.57.
Craig Erlam, senior market analyst at Oanda, said the days leading up to the election were always expected to be chaotic, but that the last couple of days had "seriously taken their toll on investor sentiment".
Mrs Clinton is under pressure after the FBI revealed it was investigating new evidence into her private email server.
The Federal Reserve decided to keep US interest rates on hold ahead of the election, but left the door open to a rise next month.
US stocks were little moved by the central bank's decision.
"With the Fed meeting, basically they just teed it up for an increase in December, so there was really nothing unusual ... This market right now is (focused) more on the election and any technical indicators," said Alan Lancz, president of investment advisory firm Alan B. Lancz & Associates.
(Close): Wall Street dropped again on Wednesday as uncertainty continued over the US presidential election.