The rapper last appeared at the dual event in 2013 and also topped the bill in 2001.
Reading and Leeds organisers have unveiled more than 70 names for the festival, which takes place between 25 and 27 August.
Muse were announced as the first headliners in December while Kasabian were added to the line-up last month.
Festival organiser Melvin Benn called Eminem's return "beyond exciting".
"His 2013 headline performance was incredible and I can't want to have him back."
Melvin Benn said the line-up, which also features south London rapper Giggs and LA rockers Haim, was "looking stronger than ever".
Other performers include Atlanta hip-hip group Migos, indie rockers Blossoms, along with Everything Everything, Charli XCX, Lethal Bizzle and You Me At Six.
Earlier this year the festivals were criticised by music fans after only one female performer was included in the initial line-up alongside 57 men.
American band Against The Current, fronted by Chrissy Costanza, have now been joined by another 16 acts that feature at least one woman, including Haim and singer-songwriter Ray BLK.
However, the festival is still dominated by men, with 80 of the remaining 97 performers being male solo artists or all-male bands.