The actress - who plays Amy Pond - will be written out in a "heartbreaking" storyline, show boss Steven Moffat 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.
Moffat 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. That story is going to be a heartbreaking one."
He said that The Doctor would be "taking a new friend", adding: "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 him.
He added: "We took over the show and we really had to hold hands and help each other through it. It's very disappointing. But this show is about change and regeneration."