The former world No. 1 Nadal, who turned 29 on Wednesday, was seeking a sixth straight and 10th overall title at Roland Garros, but the high-flying top- ranked Djokovic made sure that wasn't going to happen.
A ruthless Djokovic knocked out the sixth-seeded Nadal 7-5, 6-3, 6-1 to hand Nadal only his second-ever loss at the French (70-2). The Spaniard's previous loss at the world's lone clay court major came at the hands of Swede Robin Soderling in the fourth round in 2009.
The reigning Australian Open and Wimbledon champion Djokovic needs that French Open title to complete the career Slam, just like his contemporaries Roger Federer and Nadal have done.
Djokovic started off red-hot by grabbing a pair of breaks en route to a 4-0 lead. But Nadal got the breaks back en route to evening the stanza at 4-all.
The 28-year-old Djokovic, however, ultimately claimed the set with a third break of the 14-time major champ and the Serbian stalwart was on his way.
Djokovic broke for a 5-3 lead in the second set and consolidated the break with a hold to forge ahead two sets to love. It marked the first time in 11 trips to the French that Nadal had trailed by that margin.
The sizzling Djokovic broke Nadal again to open the third set and the Spaniard's fate was all but sealed on Court Chatrier.
The match ended on the Serb's first match point when Nadal double-faulted, as Djokovic broke the Spaniard at love to move on.
Nadal had won his last 39 matches on his beloved clay in Paris. The Spanish great won only 14 of his 37 second-serve points and misfired for 30 unforced errors on Wednesday.
"He was better than me. That's it," Nadal said of Djokovic.
Bjorn Borg holds the record for consecutive match wins at one Grand Slam event -- 41 straight at Wimbledon.
Djokovic lost to Nadal in two of the previous three French Open finals, including last year. Nadal still leads their lifetime series 23-21, including 9-4 at the Slams and a 6-1 record at Roland Garros. Djokovic hadn't beaten Nadal in a Grand Slam match since their epic 2012 Aussie Open finale and lost to the Spaniard the previous three years in Paris.
Djokovic has won his last 27 matches on tour overall, including a perfect 14-0 mark on clay this year.
Nadal had won five straight French Open titles, this following a run of four straight championships from 2005-2008. He was trying to become the first player in the Open Era to win 10 titles at a Grand Slam event.
With the defeat, Nadal is set to fall to No. 10 in the rankings; his lowest position since April 2005. Should Jo-Wilfried Tsonga beat Stan Wawrinka and reach the final, Nadal would drop to No. 11.
Djokovic's semifinal opponent, the hot third-seeded Murray, snuck past gritty seventh-seeded Spaniard David Ferrer 7-6 (7-4), 6-2, 5-7, 6-1 in an engaging affair on Court Lenglen. Ferrer was the 2013 Roland Garros runner-up to his compatriot Nadal.
Ferrer forced a fourth set against Murray after saving a match point while trailing 4-5 in the third. The Spaniard held to level the stanza, broke for a lead, and held to force the fourth.
Unfortunately for the 33-year-old Ferrer, it was all Murray in the fourth. The Scot broke for a 2-0 advantage en route to a commanding 5-0 lead.
Murray advanced in 3 hours, 18 minutes, closing out Ferrer with an unreturnable serve on his third match point.
The two-time Grand Slam titlist Murray, who is a flawless 15-0 on clay this year, is now 10-6 lifetime versus Ferrer, including 1-4 now on the dirt.
Murray will appear in his third French Open semi in five years. He's seeking a first-ever trip to the final in Paris.
Djokovic is 18-8 lifetime against Murray, including 5-2 at the majors and 2-0 on clay. The Serb bested the Brit in January's Aussie final.
Friday's other semifinal will pit the eighth-seeded Swiss Wawrinka against the 14th-seeded heavy French crowd favorite Tsonga. Wawrinka will play in his second major semifinal of the year. He lost to the eventual champion Djokovic in the Australian Open semis while trying to defend his lone career Grand Slam title.
Tsonga will play in his second French Open semi in three years. He is just the second Frenchman in the Open Era to reach multiple semis at Roland Garros.
Wawrinka and Tsonga have split their previous six career ATP matchups, including a split of two meetings at Roland Garros. The Swiss topped the Frenchman in the round of 32 in Paris in 2011 and Tsonga bested Wawrinka in the round of 16 the following year.