Duke, 60, a former banking industry executive, said in her resignation letter to President Obama that it was an honor to serve as one of the central bank's seven board members and praised the leadership of Fed Chairman Ben S. Bernanke.
Duke said she was "especially gratified to have brought my own practical banking experience and community banking perspective" to the Fed's implementation of the 2010 Dodd-Frank financial reform law.
She joined the board in August 2008, just weeks before the financial crisis hit that saw the Fed take unprecedented actions to help prevent a stock market meltdown and boost the economy.
"I believe history will judge that the Federal Reserve, under the resolute leadership of Chairman Bernanke, met every test in a thoughtful, innovative and effective way," she said in her resignation letter.
She was effusive in her praise for Bernanke, whose second term as Fed chairman expires in January. It's unclear if Obama will nominate him for another term, or if Bernanke wants to continue in the job.
Duke said she admired Bernanke's "courage and extraordinary intellect."
"His considerable personal strengths proved to be invaluable during very difficult economic times," she wrote.
Duke was appointed to the board by President George W. Bush to fill the remainder of a term that expired on Jan. 31, 2012.
She remained on the board after her end of her term, pending confirmation of a replacement by the Senate. But Obama has not nominated a replacement.
Neither Duke nor the Fed indicated her future plans.
"Betsy has made invaluable contributions to the Federal Reserve and to the country during her five years at the board," said Bernanke said.
"She brought fresh ideas grounded in her deep knowledge of the banking industry and the real-world dynamic between borrowers and lenders," he said. "I wish her the best in her future endeavors."