Obama, long an advocate of physical fitness and healthy lifestyles, will take part in the opening ceremonies July 25 at the Los Angeles Memorial Coliseum, site of the 1932 and 1984 Summer Olympics.
"Her vision of wellness, fitness and inclusion of all in sport is at the heart of Special Olympics," Special Olympics Chairman Tim Shriver said.
With about 7,000 athletes participating in 26 different sports, the nine-day Special Olympics is expected to be the largest sports event Los Angeles has hosted since the 1984 Summer Olympics.
As many as 500,000 spectators will take in the various events, all of which are free except for the opening ceremony.
The three-hour opening will be broadcast live on ESPN and feature a long list of entertainers, musicians, former Olympic champions and others joining the first lady to welcome the athletes.
"It's going to be a real celebration of our theme, which is celebrating courage, determination and joy, and creating awareness that leads to acceptance and inclusion," said Patrick McClenahan, the games' president and CEO.
The Special Olympics features athletes with intellectual disabilities competing in such sports as swimming, basketball, track and field, and gymnastics.
The opening has elements familiar to the Olympic Games, including a parade of athletes from around the world and a ceremonial lighting of a torch.
There will also be music and inspirational speeches, including performances by Stevie Wonder and Avril Lavigne. The latter plans to perform her song "Fly" publicly for the first time.
Others planning to participate are talk-show host Jimmy Kimmel, actress Eva Longoria and Olympic gold medallists Michael Phelps and Greg Louganis.