He was the principal counsel for The Louisville Courier-Journal and other Bingham family-owned media companies prior to launching his political career.

With Eleanor Roosevelt, Arthur Schlesinger, Jr., Hubert Humphrey, and others, Wyatt took a leading role in the founding and leadership of an interest group, Americans for Democratic Action.

In 1962, Wyatt was the unsuccessful Democratic nominee for the United States Senate but lost the election to the moderate Republican incumbent, Thruston B. Morton.

[3] Wyatt's mission was successful and Sukarno did not take over foreign-owned elements of the Indonesian oil industry, as had occurred in Mexico in 1938.

He resigned this position to seek another term as governor in 1971, but he was defeated in the Democratic primary by his former executive secretary Wendell H. Ford.

Vice President Hubert Humphrey had Wyatt play an important role at the 1968 Democratic National Convention, again in Chicago.

Wyatt, who twenty-four years earlier had soothed the hurt feelings of Alben Barkley, then devised a compromise over the party's platform plank in regard to the lingering Vietnam War.

He served a term as chairman of the board of trustees at Bellarmine University; a sizeable donation from the Wyatts funds a lecture series at the school.