Defensively resilient throughout their run to the last eight, Uruguay uncharacteristically gave away a couple of sloppy goals either side of half time.
France, runners-up at the European Championship on home soil two years ago, will now face either Belgium or Brazil for a place in the July 15 final in Moscow.
Both managers were forced into a change of personnel for this opening quarter-final tie, with the injured Edinson Cavani and suspended Blaise Matuidi being replaced by Cristhian Stuani and Corentin Tolisso respectively.
The absence of Cavani following his match-winning brace against Portugal was always going to be a big blow for Uruguay, but Stuani was keen to make an impression and fired wide early on from the first shot of the contest.
France were being allowed to dominate possession as the first half wore on, playing some nice intricate football on the edge of the box without finding a way through.
Fresh on the back of his breakthrough showing on the world stage against Argentina last week, the teenage forward looped his header over the bar, despite finding himself in plenty of space.
A stuttered run-up from Griezmann from a deep free kick left the Uruguayan defence disorganised, and Varane got enough on the ball from his header to find the far corner.
After becoming just the second side in seven matches to break down the Uruguay wall, France so nearly undid their hard work before the interval as Martin Caceres got away from his man, forcing an extraordinary save from Lloris, before Diego Godin smashed the rebound over the crossbar from a couple of yards out.
France had some breathing space come the hour mark as, from the first meaningful attack of the second half, Griezmann's shot caught out Muslera.
The Galatasaray keeper had kept three clean sheets in four in La Celeste's run to the final, making 10 saves in the process, but he elected to parry Griezmann's tame shot from 25 yards and the ball went right through his hands.
Uruguay's players lost their heads at that point, with matters boiling over on the field as a number of players came face to face, ending with yellows being shown to Christian Rodriguez and France's Mbappe.
That frustration continued as Les Bleus, now unbeaten in 10 matches against South American sides at the World Cup, kept things tight at the back.
Neither side looked like scoring in the final quarter of the match, bringing an end to two-time winners Uruguay's participation in this year's World Cup.
URUGUAY (4-4-2): Muslera; Gimenez, Godin, Caceres, Laxalt; Nandez (Urreta 73'), Torreira, Bentancur (Rodriguez 59'), Vecino; Suarez, Stuani (Gomez 59')
FRANCE (4-2-3-1): Lloris; Hernandez, Umtiti, Varane, Pavard; Kante, Pogba; Tolisso (N'Zonzi 80'), Griezmann (Fekir 93'), Mbappe (Dembele 88'); Giroud