The 40-year-old announced on Twitter that he was hanging up his gloves, saying he "loved every moment of it. Win, lose or draw."
Mosley lost three of his last four fights, including a dreary bout against Manny Pacquiao in May 2011 in which he mostly seemed to be avoiding the Filipino star in the ring.
His last fight was May 5 on the undercard of the fight between Floyd Mayweather and Miguel Cotto. Mosley lost a lopsided decision to rising Mexican star Canelo Alvarez.
The loss dropped his record to 46-8-1.
Mosley began boxing at age 8 and wound up winning three U.S. Amateur titles and a bronze medal at the 1990 Goodwill Games.
His professional career peaked when he won the WBC welterweight title by beating De La Hoya in 2000 before besting the popular fighter again in 2003 to claim the light middleweight title. Mosley also won the IBF lightweight belt in 1997 and was chosen fighter of the year by the Boxing Writers Association of America.