The 71-year-old Driesell missed the Panthers' 73-62 victory at Furman Thursday night while suffering from the flu.
"I woke up New Year's Day and I told (wife) Joyce, I've worked 49 years and most people retire after 25 years," Driesell said. "I'm just tired and I've got this bad cold and I'm just going to retire. I'm looking forward to not having a job. I can get up when I want to and do what I want to."
Assistant Michael Perry will take over for Driesell on an interim basis beginning with Saturday night's home game against Gardner-Webb.
One of 14 finalists last year for the Basketball Hall of Fame, Driesell has 786 career wins and is the only coach to win 100 games at four different schools. He also shares an NCAA record by taking four teams to the NCAA Tournament.
In his sixth season at Georgia State, Driesell has a 103-59 record. But his team has struggled this season with a 4-6 mark.
Known as the "Ol' Left-hander," Driesell's given name is Charles. He took all four of his schools to postseason play with 13 trips to the NCAA Tournament and eight NIT appearances.
At Georgia State, Driesell built the Panthers into a power, amassing five straight winning seasons and the school's first NCAA Tournament victory in 2001, when his club upset Wisconsin.
But it was at Maryland where Driesell left his mark. Saying he wanted to built the school into "the UCLA of the East," Driesell compiled a 348-159 record from 1969-86.
In 1970, Driesell invented "Midnight Madness," where teams begin their seasons with a practice at midnight on the first day such practices are allowed by the NCAA.
With the Terrapins, Driesell coached forward Len Bias, who later died of a drug overdose after being selected by the Boston Celtics in the NBA draft. He also recruited Moses Malone to Maryland, although Malone opted for the NBA rather than college.
Driesell was forced out at Maryland in 1986 following Bias' death. An investigation found academic problems in the basketball program and drug use among athletes.
After his departure from Maryland, Driesell stayed away from the sport for two years before returning to coach James Madison, where he went 159-111. He took the Georgia State job in March 1997.
Driesell started his coaching career at Davidson, posting a 175-65 record from 1960-69.
Maryland won its first NCAA title last season under the guidance of Coach Gary Williams.
"I played here in 1968 and Lefty came in 1970, and so I knew what it was here when he arrived at Maryland," Williams said. "When you look at guys with influence during that time, he was right there with Red Auerbach, John Thompson and Morgan Wootten, in getting this to be a basketball area.
"Lefty is one of those people who have become a very well known figure in college basketball, historically. If you say the name, 'Lefty," people know who you're talking about.
"He was a great promoter, which needed to be done at Maryland. I don't think anybody ever out-worked Lefty. If he had to stay on the job 18 hours a day, he would. He has been a great competitor no matter where he's been.
"It's unfortunate, but for Lefty to get the respect that he truly deserves, I think maybe he needed to retire. It might have taken that for people to realize the magnitude of his career. His numbers sometimes get overlooked, but he's really had a great career. He has built a winner everywhere he has ever been."