"I've been pursuing Ralph for the last 10 years," Louisville coach Rick Pitino said in a statement. "I can't tell you how excited we are that he has joined our staff and we are back together again. Ralph is truly one of the best minds in our game."
In 10 seasons at Holy Cross, Willard won 62 percent of his games, compiling a 192-117 record.
Willard's coaching resume also includes head coaching stints at Western Kentucky from 1990 to 1994 and Pittsburgh from 1994 to 1999.
"Leaving my alma mater and the players at Holy Cross was obviously a difficult decision," Willard said in the statement from Louisville's athletic department. "However, the opportunity to work for U of L and coach with Rick is very special. I'm excited about tackling the challenges a great program like Louisville will present."
Willard led Holy Cross to 20-win seasons five times and won the Patriot League title four times, earning trips to the NCAA tournament from 2001 to 2003 and in 2007, and the National Invitational Tournament in 2005.
Willard was the Patriot League coach of the year three times and is second in career coaching victories at Holy Cross.
One of the first hires Holy Cross athletic director Richard M. Regan Jr. made was Willard.
"If one had told me at the time [when Willard was hired] that Ralph would stay for 10 years and take us to the postseason five times, I would have been ecstatic," Regan said in a statement from Holy Cross. "Having said that, I had hoped he would retire here, and I am disappointed that it won't end that way."
Willard will hold a news conference on Friday.
A call to Willard's office was not immediately returned.