The popular Irish star will return to the programme to play Megan Roach for four episodes. However it will be a short return for Brenda, as Megan is set to meet her maker.
Brenda (63) starred in Casualty from 1986 until 1988 before leaving the BBC drama to further her career.
She said: "I loved Casualty, it was great. I'm back next year for four episodes. I die. I don't know if I should be telling you that, but yes, I die."
The Dublin star later explained she had already made the decision to leave the show before she won an Academy Award for Best Supporting Actress for her performance as Christy Brown's mother in My Left Foot.
She said: "People thought I left because I won the Oscar, but I had already decided to go by then. Oscar or no Oscar, Megan didn't develop in the way she was meant to.
"She started off with a wonderful sense of humour. But she lost it all and all she ever seemed to do was push a trolley and offer tea and sympathy.
"Megan was the mother we all want, full of love and understanding. I'm not a mother and never will be.
"I couldn't do her job -- ever. Just go down to the hospital and watch what they do for an eighth of the salary I earned pretending to be a nurse. It makes you blush."
Last month, the actress revealed she was recovering after a nasty fall at her home, which left her with her arm in a sling and a black eye.
She was treated at the Mater Hospital after the accident.
"I wish I had an interesting story, I was trying to think up a funny story," the actress said. "I got out of bed too quickly and fell on the floor.
"It's a tiled floor and I just crashed my head on in it."
It was a further mishap for Brenda, who was out of action following another fall at the historic Castle Leslie in Co Monaghan last Christmas.
Most recently the Irish actress played a guest role in six-part comedy series Beautiful People for BBC.
Brenda recently starred in the film Stone of Destiny, which was chosen to close the prestigious Toronto International Film Festival last year.
She has also teamed up with Olympia Dukakis for a road-trip comedy about a lesbian couple who break out of a nursing home.