He was also one of the House managers appointed in 1804 to prosecute the case in the impeachment trial of John Pickering, judge of the United States District Court for the District of New Hampshire, and, later that year, he was also appointed a House manager for the impeachment trial of Samuel Chase, associate justice of the Supreme Court of the United States.

Three of the couple's four young children died in April 1819, and Campbell wrote Secretary of State John Quincy Adams asking to be recalled and return home.

Appointed Secretary of the Treasury on his forty-fifth birthday by James Madison, Campbell faced national financial disorder brought on by the War of 1812.

Congress had failed to recharter the First Bank of the United States after its charter expired in 1811, and appropriations for the war were unavailable, so Campbell had to convince Americans to buy government bonds.

He was unsuccessful in his efforts to raise money through additional bond sales and he resigned that October after only eight months in office, disillusioned and in bad health.