The book, which is to be released on October 12, explores a world of "high stakes diplomacy and treachery”.
It features a series of terrorist attacks that throws global order into disarray. The secretary is tasked with assembling a team to "unravel the deadly conspiracy”.
Mrs Clinton is one of the world’s better known fans of mystery novels.
She is teaming up with her friend, the novelist Louise Penny, for State of Terror.
It will be jointly released by Mrs Clinton's publisher, Simon & Schuster, and Penny's, St. Martin's Press.
"Writing a thriller with Louise is a dream come true," Mrs Clinton said in a statement on Tuesday.
"I've relished every one of her books and their characters as well as her friendship.
“Now we're joining our experiences to explore the complex world of high stakes diplomacy and treachery. All is not as it first appears."
Penny, an award-winning author from Canada whose novels include "The Cruelest Month" and "The Brutal Telling," said she could not "say yes fast enough”.
"What an incredible experience, to get inside the State Department. Inside the White House. Inside the mind of the Secretary of State as high stake crises explode," she said.
"Before we started, we talked about her time as Secretary of State. What was her worst nightmare? 'State of Terror' is the answer."
Fiction writing and worst-case scenarios have become a favourite pastime for Mrs Clinton and her husband, former President Bill Clinton.
He collaborated with James Patterson on the million-selling cyber thriller "The President is Missing," and on a new novel, "The President's Daughter.”
The later will land on shelves in June.
Mrs Clinton, who was secretary of state during Barack Obama's first term, has also written a handful of nonfiction works.