"It's time to take a break."
The 67-year-old said he had reached a point where he wanted to call it a day after being with the show since its inception.
ITV said there would be no further specials beyond the ones already planned.
The ground-breaking programme was the first prime time show to offer viewers a chance to win a one million pound prize, even if it was rarely ever reached, and became a major hit around the world. It also inspired the blockbuster movie Slumdog Millionaire.
Announcing his departure in a statement, Tarrant said: "It's been a huge part of my life for 15 years and I've loved every minute of it, but it is time for me to move on from Who Wants to Be a Millionaire.
"It's been the most remarkable journey and I consider myself very fortunate to have been associated with Millionaire from its inception.
"ITV have been fantastic in their support from day one and to see its huge success has been thrilling."
The show appeared daily across ITV's schedule when it launched in 1998, and Tarrant proved be a master of building tension.
In recent years, it has been used as a platform for fund-raising celebrity specials.