Froome fell even before the seven cobblestone patches on the slick road from Ypres, Belgium, to Arenberg-Porte du Hainaut in France. Riders had known months ago about the bone-jarring course; incessant rain made it even more treacherous.
The withdrawal of the Team Sky leader left the race wide open with 16 stages still left.
Overall race leader Vincenzo Nibali wasted little time in speeding ahead, notably after he saw that his other big rival for the title this year, two-time Tour victor Alberto Contador, had trouble on the second run on cobbles.
Sensing the danger from the rain, race organizers scrapped two of the nine scheduled cobblestone patches, and reduced the stage by three kilometres (two miles). But that still wasn't enough to stop many riders from tumbling.
Froome, already nursing pain in his left wrist from a crash on Tuesday, took his third and last spill in two days about halfway through the stage. With a cut under his right eye, the Team Sky leader limped over to a team car, climbed in, and drove away.
Froome tweeted he was "devastated" to have to withdraw. "Injured wrist and tough conditions made controlling my bike near to impossible," he wrote. He wished luck to new Sky leader Richie Porte of Australia and his other teammates for the rest of the race.
"It's devastating for Chris and for the team," Sky boss Dave Brailsford said. "We really believed in Chris and his ability to win this race. But it's not to be this year.
"When you have a day like today, when you have a setback, you have to roll ahead and go again, you have to recalibrate your goals. Richie Porte came on the Tour to be the team leader No. 2, and he showed great ability to ride the cobbles the way he did."
The last time a defending champion abandoned the Tour was five-time winner Bernard Hinault of France in 1980, according to French cycling statistics provider Velobs.com.
Nibali, too, was one of several high-profile riders who crashed, recovered and excelled on the 152.5-kilometre (95-mile) route. The Italian finished third and extended his lead. He and second-place Jakob Fuglsang of Denmark were 19 seconds behind stage winner Lars Boom of the Netherlands.
"This is a special, special day for me," said Boom, who rides for Belkin Pro Cycling. "I was really looking forward to the cobblestones."
Overall, Nibali leads Astana teammate Fuglsang by 2 seconds. Cannondale rider Peter Sagan of Slovakia was third, 44 seconds back. Contador, breathing hard under a mask of mud at the finish, lost about 2 1/2 minutes to Nibali: He's 2:37 back, in 19th place. Sky's Porte was eighth overall, 1:54 back, and Valverde was 10th, 2:11 behind.
Svein Tuft of Langley, B.C., was tied for 99th in the stage, 13:51 off the lead. Christian Meier, also from Langley, was 15:23 off the pace in a tie for 117th. Tuft is 140th overall and Meier is 144th.
Nibali expressed little reaction to Froome's pullout.
"We have to be calm. The road to Paris is very long," he said. "Cycling is made of crashes, and we have to take that into account."
Others who went down but kept going included Americans Andrew Talansky and Tejay van Garderen, Spain's Alejandro Valverde, and Germany's Marcel Kittel, winner of three of the first four stages. In what was perhaps the day's most visually dramatic crash, Belgium's Jurgen van den Broeck went hurtling over his handlebars in a bend on a cobblestone patch, and tumbled into a grassy roadside.
While the chaos on the course raised questions about riding in such poor conditions — critics in social media had a field day — it made for great racing imagery: Many riders were caked in sloppy, wet mud on their faces and shins, their biceps jiggling as they held their handlebars. A mix of sweat, rain, mud and drool dropped from many chins. Many looked as if they'd ridden through a shower of chocolate pudding.
The race heads to Champagne country on Thursday, with a mostly flat 194-kilometre (120-mile) run from Arras to Reims in Stage 6.