Meyer, 46, also resigned last year before the Sugar Bowl, but then rejoined the team. He is retiring from coaching and the decision is not health related, sources told FanHouse.
The school has confirmed the move and a press conference will be held Wednesday night.
Florida is headed to the Outback Bowl in Tampa, Fla., on Jan. 1 to play Penn State where Meyer will coach his last game against Penn State's Joe Paterno.
"I have been a Division I football coach for the last 25 years and, during that time, my primary focus has been making a difference in the lives of the young men I have been so fortunate to have coached and building championship programs," Meyer said in a statement. "At this time in my life, however, I fully grasp the sacrifices my 24/7 profession has demanded of me, and I know it is time to put my focus on my family and life away from the field.
"The decision to step down was a difficult one. But, after spending more than two decades motivating and celebrating the young men I've been so proud to coach, I relish the opportunity to cheer for my three terrific kids as they compete in their own respective sports. I know how fortunate I am to be in a position to make this choice and to have a family that is as loving and supportive as my amazing wife and children have always been. My family has shared both the commitment and the sacrifice required to coach at this level for so long and I would not have enjoyed the success I have had without their support."
David Whitley: This Time It's For Real
Meyer won two BCS national titles in his six years at Florida (2006 and 2008), two SEC championships (2006 and 2008), three SEC Eastern Division crowns (2006, 2008 and 2009) and led UF to six-consecutive January bowl games, including three BCS bowl games.
He also was named Sporting News and Sports Illustrated "Coach of the Decade" in December of 2009.
"I am enormously grateful to the University of Florida and our tremendous fans for giving me the incredible opportunity to lead the Gator football program," Meyer said in the statement. "The support provided by school president Bernie Machen and athletics director Jeremy Foley has been an invaluable part of all that we have been able to accomplish over the last six years.
"I have exceptional regard for my coaching staff who has always shared my passionate commitment to winning and to guiding the development of the young men of Florida football. Most importantly, I will be forever grateful to the student-athletes I have had the honor to coach and from whom I have learned so much. I will profoundly miss coming to campus every day to coach this team, but I will always be a Gator at heart, and I am confident that the program will continue to reflect the highest ideals of the University of Florida and collegiate sports."
Florida athletic director Jeremy Foley said it has been "an honor and privilege" to have Meyer coach the Gators the past six seasons.
"The championships, the mentoring of young men and his commitment to the University of Florida have indeed been special," Foley said. "As good of a coach as he is, he's a better person and a great friend. He has given everything he has to this institution and we are grateful for the experiences. It a chapter in our history that is closing, but I know Urban wants to remain involved with the University and the Gainesville community. He absolutely loves the Gators."
In six seasons, Meyer was 64-15, which included a school record 22 consecutive victories.
"As I have said many times, Urban Meyer's integrity and commitment to his players and the University of Florida are beyond reproach," Florida president Bernie Machen said in a statement. "He leaves an outstanding legacy, on the field and in the classroom. I know that all Gators wish nothing but the best for Coach Meyer as we recognize his extraordinary achievements with a great sense of pride and appreciation."
Last season, Meyer, who was admitted to a hospital because of chest pains following the 2009 SEC championship game, stepped down because of health concerns. But he rejoined the team a day later.
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Brett McMurphy is a national college football writer for FanHouse. Contact him at email@example.com or please follow at Twitter.com/BrettmcmurphY