The actress, 24, will be written out in a “heartbreaking” storyline, programme boss Steven Moffatt said.
A new companion for The Doctor is being lined up, but producers said they would give no clues about their identity.
Gillan and her screen husband Arthur Darvill – who plays Rory – will both be written out.
The Scottish actress, who will soon be seen in a BBC drama as model Jean Shrimpton, has had a starring role for two series and has become hugely popular. Moffatt said: “The final days of the Ponds are coming. It’s during the next series. I’m not telling you when and I’m not telling you how.”
Moffatt said The Doctor would be “taking a new friend”. “I’m not going to tell you anything about he, she or it.”
Matt Smith said he would miss his co-star, who joined the programme at the same time as himself. “We took over the show and we really had to hold hands and help each other through it. It’s very disappointing.”
But he added: “This show is about change and regeneration.”
In June last year, Gillan hit back at criticism over Amy’s sexy demeanour – saying feminism was not the issue any more. The flame-haired Scot claimed her character’s mini-skirts are typical of what young women like to wear.
The series came under fire from some viewers for a scene in which Amy tried to seduce the Doctor, but Gillan said they were unlikely to get together romantically as he sees Amy more like an annoying younger sister.
It is understood the decision for Gillan to leave the show was mutual.
Moffatt was speaking at a screening of the Christmas edition of the show which will be broadcast on December 25.