Cassandra Rose Clarke was born on September 21, 1983, in south Texas. She graduated from the University of St. Thomas in Houston with a B.A. in English in 2006, and received an M.A. in Creative Writing from the University of Texas at Austin in 2008. In 2010 she attended the Clarion West Writer’s Workshop in Seattle, where she was a recipient of the Susan C. Petrey Clarion Scholarship Fund.

In 2009, Clarke produced her first published work, the short story "The Cowboy's Wife", which was published in the Summer 2009 issue of Zahir. She published several additional short stories in the next few years, and in 2012 published her first novel, the young-adult fantasy The Assassin's Curse. Curse was named one of the Best Teen Books of 2012 by Kirkus Reviews. Clarke wrote two sequesl to the novel: The Pirate's Wish (2013) and Magic of Blood and Sea (2017) as well as additional novels and short fiction in the Assassin's Curse universe.

Clarke published her first novel for adults, The Mad Scientist's Daughter, in early 2013. It tells the story of Cat Novak, a young woman tutored by an android named Finn, acquired by her scientist father and with whom Cat eventually falls in love. The novel was nominated for the 2014 Philip K. Dick Award. In 2015, Clarke released her second adult novel, Our Lady of the Ice, a science fiction story with steampunk elements and a definite noir flavor, set in an alternate Antarctica which has been colonized chiefly by South Americans. Our Lady was nominated for the 2015 Romantic Times Reviewers Choice Award in Science Fiction. In 2017 she released the space opera Star's End, and a YA fantasy, Forget This Ever Happened in 2020. Her latest novel, a paranormal romance titled Singing With The Devil, and its sequel Demon Song, were released as e-books in 2022. Another fantasy novel, The Beholden also came out in 2022.

She has written several tie-in novels for media universes, including two novels set in the world of Halo (Battle Born and Meridian Divide, both 2019), and one set in the world of Star Trek: The Next Generation: Shadows Have Offended (2021). Clarke is also an accomplished genre poet. Her 2018 poem "For Preserves" was the runner-up for the 2018 Rhysling Award for Long Poem. Her poetry collection Sacred Summer (2020) was a finalist for the 2021 Elgin Award for Best Book.