Glenn Murphy will resign as its chairman and chief executive in February after being in the role for over seven years.
He will be replaced by its current digital leader Art Peck, who has been with the retailer since 2005.
News of the management shakeup came as the firm reported weak same-store sales in September.
The company said weak sales in its Gap brand were expected to hurt margins in the third quarter.
The San Francisco based firm also owns clothing retail chains Old Navy and Banana Republic.
Gap's market value has almost tripled since Mr Murphy, 52, became its leader in July 2007, while its earnings have more than doubled in that period.
But, the retailer's revenue growth has struggled in a competitive US market, which resulted in announcements about expanding in emerging markets like India and China this year.
In August, the company said it would open 40 stores in India and add another 30 in China to take its total in that country to 110.
Mr Murphy made the decision to retire, because he could not commit to lead the company for the next several years, he told analysts during a conference call.
Art Peck, 58, was the head of Gap's North America operations in 2011 and 2012. The region accounts for more than three-quarters of the retailer's revenue.
The chief executive officer of US retail clothing chain Gap is stepping down, the company said on Wednesday.