The 56-year-old corporate lawyer has monitored contestants' progress during tasks alongside Nick Hewer since the programme launched in 2005.
Mountford will now concentrate solely on her PhD in papyrology, leaving Sir Alan Sugar to find a new assistant for the show's sixth run next year.
Writing in The Daily Telegraph, she confirmed: "This will be my last series on The Apprentice. I have really enjoyed making the series and it will be a real wrench to say goodbye.
"But making The Apprentice takes up a large chunk of time each year, and that's time I could, indeed should, be spending on my studies. I am working on a PhD in papyrology at University College London, studying documents found in Egypt and written in ancient Greek.
"I have not made nearly as much progress as I would like over the last few years - and I want to finish my degree before I need a Zimmer frame to get up on the platform to receive it."
Mountford will make her final appearance in the series five final, which airs on BBC One tomorrow night.
A show insider told The Sun: "This will come as a big blow to Sir Alan and the millions of viewers. Margaret and Nick have almost as big a following as Sir Alan. She is very sad to be leaving but she feels the time is right."