At the conclusion of his political career in 1947, Hannegan and his business partner Fred Saigh purchased the St. Louis Cardinals, a Major League Baseball team.

Hannegan supported Truman for re-election to the U.S. Senate when he was challenged in the Democratic primary by Governor Lloyd C. Stark and Maurice M. Milligan, who both sought credit for bringing down Pendergast.

Shortly before the 1944 Democratic National Convention, Roosevelt famously sent Hannegan a letter stating he would be "happy to run with" either Truman or Supreme Court Justice William O. Douglas.

Hannegan later joked he wanted his tombstone inscribed with the words "Here lies the man who stopped Henry Wallace from becoming President of the United States.

"[2] Though plagued with ill health for much of his tenure as party chairman, Hannegan emphasized voter turnout efforts in Roosevelt's 1944 re-election campaign and prevented an upset by Thomas Dewey, who won a surprising 46 percent of the popular vote that year.