Young Slovak sensation Peter Sagan avoided the cross-the-road pile-up to claim his third stage win in a sprint finish. Fabian Cancellara of Switzerland also rode clear of the mess to retain the yellow jersey.
The 207.5-kilometre ride from Epernay to Metz got off cheerfully in Champagne region of France as roadside fans held aloft glasses of bubbly to prod on the riders.
But as the pack picked up speed to chase four breakaway riders with about 26 kilometres to go, at least two dozen riders spilled across a rural road — leaving many downed, dazed or looking for team staffers for support in a jumble of injured riders and bikes on the ground.
"It was like a trench hit by a (grenade) when I entered the crash to give my bike to Bauke," said Rabobank's Laurens Ten Dam on his Twitter account of the crash and his teammate Bauke Mollema. "Lots of blood and screaming. Carnage."
Hesjedal's Garmin team, riding in formation, bore the brunt of the damage.
Hesjedal — the winner of the Giro d'Italia in May — injured his knee and lost more than 13 minutes in the hunt for the title, all but quashing his podium ambitions. He had started the stage in ninth place, 18 seconds back, but now sits 108th.
"I got caught up in the crash like countess others and immediately realized that my left leg wasn't good. Once I got up and on a bike, I couldn't pedal with any force, the pain was too much," Hesjedal said in a statement. "The team helped me get to the line, but just getting there was all I was able to do.
"At that point, it was just about getting to the finish."
Hesjedal, who is scheduled to race for Canada at the London Olympics, said he would work with Garmin's medical team to determine if he can continue.
"It's the Tour so you want to do everything you can, but we have to wait and see," he added. "That was one of the worst crashes I've ever seen and I hope that everyone else who went down is OK."
Earlier, teammate David Millar said he was worried Hesjedal would be forced to withdraw.
"I think Ryder is out," Millar said. "We'll see, but he is in a bad way."
Garmin riders Tom Danielson of the United States (collarbone, hip, elbow) and Johan van Summeren of Belgium (concussion) were also evacuated to the Metz hospital.
"It was the scariest crash I've ever been in," said Millar, who had black marks of chain-grease all over his arm.
He added the riders were going at least 70 kilometres an hour when the crash occurred.
"God knows how it happened," Miller said.
Although Hesjedal went down, two other contenders, Bradley Wiggins and defending champion Cadel Evans, escaped unscathed.
Overall, Cancellara leads ahead of Wiggins — a pre-race favourite, hoping to become the first Briton ever to win the Tour — by seven seconds. Evans climbed one spot to sixth, and is now 17 seconds back, after Edvald Boassen Hagen of Norway lost more than two minutes in a crash.
The peloton, led by sprint teams from Orica-GreenEdge and Lotto-Belisol, then caught four breakaway riders with just over a kilometre to go. Andre Greipel of Germany, who is hoping for a third consecutive stage win, was the first to make a move in the final section, but couldn't resist Sagan's surge.
"I was in a good position, I kept it and then nothing hampered my effort," Sagan said. "I took Greipel's wheel and everything went according to plan."
Garmin had one bright spot: U.S. rider David Zabriskie launched an attack five kilometres after the start, and was joined by three other riders.
The four breakaway riders collaborated well and built a four-minute lead over the peloton before Cancellara's teammates moved to the front of the bunch to set up a faster tempo.
But the day's first crash 35 kilometres into the stage that involved at least 20 riders upset the chase, and the escapees' advantage grew to more than six minutes after 42 kilometres.
Among those caught in that crash were Rabobank team leader Robert Gesink, winner of the Tour of California this year, and former Spanish Vuelta champion Alejandro Valverde of Spain. But all the riders involved in the pileup to have gotten back on their bikes.
Another minor crash slowed the peloton at 60 kilometres to go, with Greipel hitting the ground.
Zabriskie, who earned honours as the stage's most competitive rider — held out alone leading the breakaway until sprinters from the depleted front pack overtook him.
The race moves into the mountains on Saturday with a 199-kilometre ride to the ski resort of La Planche des Belles Filles in the Vosges. The stage features the Tour's first category-one climb, a nasty six-kilometre ascent with the final few hundred meters at an average gradient of 14 per cent.
Associated Press Writers Greg Keller and Samuel Petrequin contributed to this report.