The series - a co-production between Starz and BBC Worldwide - will be written by Man of Steel scribe David S Goyer.
St Trinian's 2 star Riley will play a 25-year-old Leonardo da Vinci, described as "an artist, inventor, swordsman, lover, dreamer and idealist".
"Leonardo had to be smart, witty and incredibly confident - without coming across as arrogant," explained Goyer. "He also had to be tormented, because, as a true visionary and polymath, he was ostracised for his ideas as much as he was celebrated.
"Tom came in and was able to effortlessly combine all of those elements. As soon as he finished his audition, we knew we'd found our man."
"Da Vinci is a near mythic figure in history that fascinates people to this day," added Starz managing director Carmi Zlotnik.
"It is quite an undertaking to bring to life a role that comes with so many pre-conceived notions. Tom showed us that there are many dimensions to this man yet to be explored, and, at the same time, make him believable, surprising and unique to a worldwide audience."
Riley has previously appeared in episodes of Marple and Lost in Austen. He will also reprise his role as Lawrence Shepherd in the second series of ITV1's medical drama Monroe.
Doctor Who's Julie Gardner will executive produce Da Vinci's Demons alongside BBC Worldwide Productions' head Jane Tranter.
The eight-part series will enter production in summer 2012 and will air on Starz in 2013.
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