The Flamanville 3 European Pressurized Reactor in Normandy started providing electricity to French homes at 11.48 am (1048 GMT) Saturday, the EDF power company's CEO Luc Remont said in a statement.
"Great moment for the country," President Emmanuel Macron said in a statement on X, calling it "one of the world's most powerful nuclear reactors."
"Re-industrialising to produce low-carbon energy is ecology French style," he added.
The EPR, a new generation pressurised water reactor, is the fourth to be finished anywhere in the world.
Remont of EDF called the event "historic."
"The last time a reactor started up in France was 25 years ago at Civaux 2," he said, referring to the Civaux power plant in southwestern France.
The connection was initially scheduled to take place Friday.
It is the most powerful reactor in the country at 1,600 MW. Ultimately, it should supply electricity to upwards of two million homes.
The start-up comes 12 years behind schedule after a plethora of technical setbacks which saw the cost of the project soar to an estimated 13.2 billion euros ($13.76 billion), four times the initial 3.3 billion euro estimate.
The start-up began on September 3, but had to be interrupted the following day due to an "automatic shutdown". It resumed a few days later.
Generation has been gradually increased to allow the reactor to be connected to the electricity network.
Nuclear power accounts for around three fifths of French energy output and the country boasts one of the globe's largest nuclear power programmes.
That is in stark contrast to neighbouring Germany, which exited nuclear power last year by shutting down the last three of its reactors.
Macron has decided to ramp up nuclear power to bolster French energy sustainability by ordering six EPR2 reactors and laying options for eight more, that could cost tens of billions of euros.