The fourth-seeded Serb, tipped as the man who could deny Rafael Nadal a record fifth consecutive title after snapping at the Spaniard's heals throughout the claycourt season, instead became the biggest name to tumble out.
Djokovic hopes were snuffed out 6-4 6-4 6-4 in the third round by Germany's Philipp Kohlschreiber before women's second seed Williams created some drama of her own.
Six years after accusing the now-retired Justine Henin of "lying and fabricating" in a controversial semi-final defeat in Paris, the American laid into Maria Jose Martinez Sanchez after dispatching the Spaniard 4-6 6-3 6-4 to reach the fourth round.
Martinez Sanchez grabbed an ill-tempered opening set after breaking in the fifth game of the opening set with a controversial shot which appeared to have ricocheted off her arm on its way over the net.
"The ball did touch her 100 percent on her arm," said Williams, who struggled with breathing problems in the match.
"The rules of tennis are when the ball hits your body, then it's out of play. You lose a point automatically. So the ball hit her body, and therefore, she should have lost the point instead of cheating.
"It was clearly my point ... I've never sunk low."
While Williams was clearly fired up, Djokovic appeared to be dragging dead weights around his ankles against Kohlschreiber.
"My legs were really stuck ... I wasn't moving," summed up the Serb, who also fell out of a three-way race to secure the world number two spot at the end of the major.
Women's fourth seed Elena Dementieva's hopes of winning a maiden grand slam title also fizzled out after she was beaten 6-3 4-6 6-1 by Australian Samantha Stosur.
Path Cleared
Djokovic's defeat has cleared a big obstacle from Roger Federer's path as he seeks to reach his fourth successive final.
The Swiss did not have it all his own way on Saturday and faced a few anxious moments before navigating past plucky Frenchman Paul-Henri Mathieu 4-6 6-1 6-4 6-4.
As she has done so often, Williams provided a big talking point on day seven of the championships.
At break point in the fifth game, the younger of the Williams sisters slammed the ball into Martinez Sanchez.
The Spaniard lifted her racket to try to whack the ball back but Williams was convinced otherwise.
The 2002 champion protested to chair umpire Emmanuel Joseph and having failed to overturn his decision, she flashed her eyes and warned "she'd better not come to the net again".
Martinez Sanchez refused to get drawn into a slanging match.
"I put the racket up. The ball was in and it was a point for me. It didn't hit me or my body," said the 26-year-old.
"To say I'm a cheat is stupid. I'm not commenting on it."
"I'd like to keep going. I don't even have anything else to do next week. I'd like to stick around," beamed the American.
While Roddick was enjoying a French Open renaissance, Dementieva was already looking ahead to Wimbledon.
The Russian was lucky to survive the previous round as she was trailing by a set when Australian Jelena Dokic was forced to quit injured but there was to be no respite on Saturday.
"I'm far away from being in the good shape," said the Olympic champion, who was the second big name to fall from the women's side after third seed Venus Williams went out on Friday.
Romania's Sorana Cirstea upset 10th seed Caroline Wozniacki 7-6 7-5. Svetlana Kuznetsova's pursuit of a maiden Paris title gathered momentum when she beat Hungary's Melinda Czink 6-1 6-3. Next up for the Russian will be 12th seed Agnieszka Radwanska.
Serbian fifth seed Jelena Jankovic did not allow Australian Jarmila Groth to settle in a 6-1 6-1 hammering.
Fifth seed Juan Martin del Potro of Argentina, number nine Jo-Wilfried Tsonga and his fellow Frenchman Gael Monfils all progressed.
