The donation is part of a pattern of bipartisan giving from the GOP lawmaker. Donations to Democrats include to former Louisiana Gov. Kathleen Blanco (D) in 2003 and 2004.
Cassidy is facing Tea Party candidate Rob Maness (R) as well as Landrieu in the all-party primary, and the unusual donation could undermine his credibility with the base and in attacking Landrieu.
Cassidy argued the donations came before Landrieu moved to the left.
"Mary claimed she was going to represent Louisiana and not D.C. Then she got elected and fell into partisan politics," he said in a statement to The Hill. "Now she votes with Barack ObamaBarack ObamaObama the 'X' factor of the 2016 cycle How did Hillary Clinton do? Pundits react to speech FULL SPEECH: Hillary Clinton closes out Democratic convention MORE 97 percent of the time and cast the deciding vote for Obamacare. Now she supports anti-energy candidates who are opposed to our energy industry. Louisiana hasn't left Mary, Mary has left us."
This post was updated at 9:10 p.m.