Both second-half goals came from France left-back Patrice Evra's side of the defence as Germany fought back after Mathieu Valbuena had opened the scoring on the stroke of half-time.
Valbuena headed home from close range in the 44th minute after Karim Benzema's free-kick bounced off the bar, but Muller slotted past Hugo Lloris early the second half and Khedira wrapped it up from Mesut Ozil's pass with 17 minutes left.
Real Madrid striker Benzema missed a clear chance in the first half and has not scored for France in his last 10 appearances.
France, reeling following a poor run that lasted from 2008-12, drew 1-1 with Spain in a World Cup qualifier and beat Italy 1-0 in a friendly in their last two outings but the world's second-ranked team proved a bridge too far.
Germany were without midfielder Bastian Schweinsteiger, striker Miroslav Klose and Borussia Dortmund trio Mario Gotze, Marco Reus and Marcel Schmelzer, but they still dominated possession on a cold Parisian night.
They became the first German team to beat France since East Germany's 1-0 win at the Parc des Princes in a Euro 88 qualifier in November 1987. That year, West Germany also beat Les Bleus, 2-1 in a friendly in Berlin with goals by Rudi Voller.
France struggled in midfield but a lively Franck Ribery repeatedly threatened the German defence and Valbuena was also influential.
"We put a good tempo into the game, we had good organisation which helped us win a lot of the ball," German coach Joachim Low told a news conference.
"We were the best team tonight."
His counterpart Didier Deschamps said the teams had been "blow-for-blow" for most of the encounter, the Frenchman left to rue his side's errors and Germany's killer instinct.
"We showed some interesting things offensively but we made some mistakes and Germany showed they have great qualities. They are fast on the break."
French president Francois Hollande and German chancellor Angela Merkel attended the game as Paris and Berlin celebrate the 50th anniversary of the Elysee treaty that sealed the post-war co-operation between the two countries.
Players from the 1982 World Cup semi-final between France and Germany were invited and among them was keeper Harald Schumacher, who was booed by the Stade de France crowd 31 years after a violent challenge on French defender Patrick Battiston during a game Les Bleus lost on penalties.
Bacary Sagna, making his comeback for France with his first appearance since September 2011, broke down the right flank and picked out Moussa Sissoko in the area, only for the Newcastle United midfielder to fluff his attempt.
Khedira's low shot from just outside the box went just wide in the fourth minute as Germany got off to a confident start.
Three minutes later, Mesut Ozil collected a through ball from Muller but Lloris saved well with his outstretched foot.
Per Mertesacker's header was tipped on to the bar and over by Lloris in the 17th minute.
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