Zugaza, 52, has decided to return to his previous job as director of Bilbao's Fine Arts Museum, which he held between 1995 and 2001, the Prado said in a statement.
The Madrid museum, the home of masterpieces by Francisco Goya and Diego Velazquez, said Zugaza had told the culture ministry that he had achieved his goals and is "grateful for the all the support he received".
Zugaza took charge of the Prado in 2002, vowing to double the number of visitors to the museum.
Under his watch visitor numbers jumped from 1.7 million in 2002 to nearly 2.7 million last year.
The museum hosted several blockbuster exhibits, including a display last year of the most and best works by Dutch Renaissance master Hieronymus Bosch which drew just under 590,000 visitors.
Zugaza oversaw a transformation of the Prado, opening in 2007 a modernist new annex which offers visitors plenty of natural light and blends in with the original gallery built in the early 19th century.
The extension and renovation of the museum - the biggest in its history - allowed it to show some 400 additional paintings alongside the 1,000 that were already on display in the permanent collection.
Last week the Prado announced that British architecture superstar Norman Foster has been selected to renovate a 17th century building for another extension to the museum to be finished for the museum's bicentenary in 2019.
Once Spain's Army Museum, the Prado acquired the building last year with the aim of increasing its exhibition space.