The Serbian has shot up the rankings in recent months to 77th in the world, and will continue to climb after defeating Isner 6-4 6-7 (2-7) 7-6 (7-5), as a final against Jack Sock or Julien Benneteau awaits.
"This one is going to sting because I knew I was the highest-ranked player in the semifinals, " he said.
Unexpectedly, Isner's booming serve then let the world number 14 down, as he gave up two mini-breaks.
Isner, meanwhile, once again fell short of the title after the American was soundly defeated in the finals past year by Andy Murray. Isner's 31st ace steadied him but a superb return to Isner's feet on the next point gave Krajinovic match point on his serve. Isner has won 12 ATP titles and has $12,317,944 in career earnings.
The 25-year-old reached the last four after world number one Rafael Nadal withdrew from the tournament before their quarter-final on Friday with a right knee injury.
It was all set up for two Americans to make Paris their own by reaching the final of the year's last ATP Masters 100 event. At nearly 36 years of age, the veteran Frenchman will certainly never get a better chance to win that elusive title, and doing so in his home country in a massive tournament would be a magnificent achievement, regardless of the quality of the field this week.
With Isner serving at 4-4 and 40-30 in the ninth game of the second set, the match was halted for six minutes when several medical staff attended to a female spectator, who was then taken away. The second set saw commanding holds from both players and there were no break points, it went into a tie break and it was a must win for Isner, who has vast experience in these situations, unlike Krajinovic. 'But I can not talk about that now; it is tough enough for me to pull out from here'.
Reaching the final is particularly sweet for a top-10 junior whose promising career was held back by an extra bone in his right wrist that needed treatment, following on from a right shoulder operation in 2011.
"So it was hard for me, but my family stayed with me". "I knew that one day everything will come back".
"I break top hundred a couple years ago and then all of a sudden I have an extra bone in my wrist, " he said.
'We all know Rafa, once he says he's going to do something he sticks to it, ' Forget said.