Fabien Galthie's choice to make 12 changes from the team who beat three-time champions New Zealand in the curtain raiser last Friday could have backfired as France were never fully in control at the Pierre Mauroy stadium, sealing the win in only the final minutes on Thursday.
They prevailed with tries by Antoine Hastoy, Peato Mauvaka and Louis Bielle-Biarrey with the rest of the points coming from the boot of the reliable Melvyn Jaminet, while Uruguay scored two fine tries by Nicolas Freitas and Baltazar Amaya as Felipe Etcheverry could only kick a conversion.
France lead Pool A with eight points, three ahead of Italy. New Zealand face Namibia in Toulouse on Friday.
"Credit to Uruguay. They played with so much passion and heart. It was the second win for us in this competition which was important," France general manager Raphale Ibanez said.
"We made a few mistakes with ball in hand and it was difficult for us to play with good structure. We didn't take the points with ball in hand at the end of the second half."
Uruguay captain Andres Vilaseca was beaming with pride.
"I'm so proud of my team. I couldn't ask for a better team to lead. That's the truth," he said.
"Today, 10 minutes left of the game, we were fighting against France, one of the best teams in the world, playing at their home ground. This is only the beginning for us."
It was Uruguay's entrance in this World Cup, and they started their campaign with great fanfare, an early try by Freitas silencing the home crowd.
The winger touched down in the corner after collecting a cross-field kick from Felipe Aliaga, showing the South Americans have more to offer than courage and grit.
The hosts responded quickly after torturing their opponents in the scrum, with Hastoy going over and Jaminet converting to put them 10-5 ahead.
Over confident, France thought it was the early break they needed, but the visitors had other ideas.
Romain Taofifenua was sin-binned for a dangerous tackle and Uruguay threatened through Freitas and were denied a try after Tomas Inciarte was harshly ruled to have blocked a French tackler.
Undisciplined in the scrum and bothered by Uruguay in the mauls, France were only 13-5 ahead at half-time and the visitors continued their effort after the break.
They reduced the arrears with a superb try by Amaya, who evaded a tackle before touching down in the corner.
Les Bleus were somehow lucky to extend their lead shortly afterwards as Mauvaka scored a try after Felipe Etcheverry's kick in the traffic bounced onto the back of a teammate and into the path of the French hooker.
Jaminet's conversion put them 20-12 ahead and Bielle-Biarrey, at 20 the youngest French player to take part in a World Cup, put the result beyond doubt seven minutes from time when he dived over on the open side.
Sekou Macalou had the bonus-point try denied, and it was a fair conclusion to an entertaining match during which France conceded a woeful 15 penalties.
