With just over 70km remaining the 29-year-old cyclist crashed for a second time during the day’s wet conditions.
Froome had yet to reach the first of several cobbled sections measuring 13km that fellow Sky teammate Geraint Thomas had predicted would prove arduous for riders.
After consulting Team Sky doctors, Froome shook his head and hobbled into the team car, marking the end of his attempt to again win the yellow jersey he received last year in Paris.
Just the day before, Froome fell off his bike during the fourth stage, requiring him to wear a splint on Wednesday’s race.
The Kenyan-born Brit was one of numerous riders to crash on the152 km stretch from Ypres, Belgium to Arenberg Porte du Hainaut.
Television cameras missed the fall but a scratched up Froome was shown with a torn jersey and shorts after his first plummet.
Froome was in seventh position at the start of the stage, just two seconds behind race leader Vincenzo Nibali.