The 71-year-old Dublin actress, who starred in The Guard and Yes Man, has joined Canadian actress Mia Kirshner, who starred in The Vampire Diaries, in the new series for US cable channel Syfy.
Fionnula is scheduled to begin production on the pilot early next month in Toronto.
The series is set in the near future and will depict a completely transformed planet Earth, inhabited by the survivors of a universal war.
Fionnula will play Nicky, the popular ex-mayor of the town of Defiance, who is a mentor to her successor, played by Amanda (Julie Benz).
Kirshner will play Kenya, a woman devoted to the town.
The series, developed alongside an online video game, is written and executive produced by Rockne S O'Bannon, Kevin Murphy and Michael Taylor, for Universal Cable Productions.
Defiance will be broadcast on Syfy next year. The role comes some two years after Ms Flanagan was honoured with a Lifetime Achievement award at the Irish Film And Television Awards (IFTAs).
Fionnula, who made her screen debut in a 1967 film version of Ulysses, also had a recurring role in hit TV series Lost.
IFTA chief executive Aine Moriarty described Ms Flanagan as "a wonderful representative, internationally, of Ireland's film and television industry".
Ms Flanagan said she was "bowled over" by the award..
"It is a great honour to be invited to join the ranks of the gifted former recipients," she said.
Born in Dublin in 1941, the actress trained at the Abbey and London's Old Vic.
Director Terry George cast Ms Flanagan in her most acclaimed role, as the mother of a hunger striker in the film Some Mother's Son, opposite Helen Mirren.