They already have a one-year-old daughter, Max, who was conceived following several miscarriages.
“After our difficult experience having Max, we weren't sure what to expect or whether we'd be able to have another child,” Mr Zuckerberg wrote in a post on Facebook.
“When Priscilla and I first found out she was pregnant again, our first hope was that the child would be healthy. My next hope was that it would be a girl.
"I cannot think of a greater gift than having a sister and I'm so happy Max and our new child will have each other.”
He added: “I grew up with three sisters and they taught me to learn from smart, strong women. They weren't just my sisters but some of my best friends. They've gone on to write books, excel at performance, music, sports, cooking and their careers. They showed me how to compete and still laugh together afterwards.”
“Priscilla grew up with two sisters and they taught her the importance of family, caring for others and hard work. They supported each other as first generation college students and in their careers in medicine and business. They have so many inside jokes — the kind only siblings can understand.”
He ended his post: “We are all better people because of the the strong women in our lives — sisters, mothers and friends. We can't wait to welcome our new little one and do our best to raise another strong woman."
After their daughter Max was born in December 2015, Mr Zuckerberg and Ms Chan — who met at Harvard university and married in their garden in 2012 — announced a philanthropic initiative to give away 99 per cent of their wealth. Mr Zuckerberg then transferred 99 per cent of Facebook shares to the newly established Chan Zuckerberg Iniative.
At the time, The Independent and other media reported that the vehicle was not a charity, but a limited liability company owned and controlled by Mr Zuckerberg. As a private company, the Chan Zuckerberg Initiative can spend its money on whatever it wants - including private, profit-generating investment.
In a post on Facebook, Mr Zuckerberg said that the decision to register as a company gave the Chan Zuckerberg Initiative more flexibility.
"By using an LLC instead of a traditional foundation, we receive no tax benefit from transferring our shares to the Chan Zuckerberg Initiative, but we gain flexibility to execute our mission more effectively," he said.