The result means the Netherlands can win the group if they draw in Gelsenkirchen against Germany on Monday, usurping the last two World Cup winners to advance to next June's Nations League finals.
The Netherlands could still win the group and earn a spot in the Nations League final, but it would take a win Friday over the Netherlands and a win over Germany later in the month.
It was a first defeat for France following their World Cup success in Russian Federation and, without a string of Lloris saves, the scoreline would have been more emphatic.
The Dutch are a point behind leaders France, who only needed a draw themselves on Friday to qualify for the knockout stage in their last match of the group but came up way short.
Wijnaldum broke the deadlock just a minute before halftime with his 10th global goal in his 52nd appearance for the Netherlands.
Wijnaldum was first. He thumped home a rebound after De Jong crossed from the left, his pass floating just over Steven Nzonzi and landing at the feet of Ryan Babel.
Depay doubled the lead with a "Panenka" penalty in stoppage time, chipping the ball over Lloris to complete a memorable victory.
"It's the first time with these guys, I'll compliment them, it's a learning opportunity for us, we're not together for so long, Germany is at full strength, I'm proud of the boys". The score could have been even more flattering for the Dutch.
The Germans did at least enjoy a 3-0 friendly win against a depleted Russian Federation on Thursday night, although the result was hardly something to shout abut given Low's current woes.
At the same time, the Dutch defense held Mbappe in check.
A depleted France arrived in Rotterdam after injuries sidelined Paul Pogba, Anthony Martial, Benjamin Mendy, Thomas Lemar, Lucas Hernandez and Thomas Lemar.
The Dutch meanwhile peppered Lloris' goal from the off, with Wijnaldum forcing the France keeper's first save with just a minute on the clock following an impressive burst from star turn Depay. De Jong was denied in extra time by Lloris, then Depay finally made all the pressure pay with his penalty for his 13th global goal.
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