Zverev's 6-3, 7-6 (7/4) win against the Dane sent the 27-year-old to his second ATP 1000-level final of the season after his victory in Rome in May.
World number 18 Humbert, who downed world number two Carlos Alcaraz in the last 16, overcame Russian Karen Khachanov 6-7 (6/8), 6-4, 6-3 after the 2018 Paris champion suffered a thigh injury in the final set.
"I feel like I made it a little difficult for myself but he (Rune) is a champion," said Zverev.
"It is probably his favourite tournament and favourite court, but I am happy to be in my second final here."
Zverev previously made the Paris final in 2020 but lost in three sets to Daniil Medvedev.
For 2022 champion Rune, the loss put an end to his outside hopes of reaching the ATP Finals in Turin, which run from November 10-17.
Zverev, standing at 198cm, relied on his big first serve and the speed of the surface at Paris' Bercy Arena to carry him through his service games.
Rune, on the other hand, misfired regularly on his first serve and lacked fluency with his groundstrokes as he gave the German a 3-1 lead in the first set.
The 21-year-old then raced to 15-40 in the next game but was again let down by his backhand as he sent two shots long and an attempted pass wide as Zverev recovered to consolidate.
Despite leading 4-1, the 2024 French Open runner-up was also unconvincing from behind the baseline as the unforced errors accumulated for both players.
However, Zverev could always rely on his serving to carry him through as he claimed the first set.
Neither Rune nor Zverev challenged on serve at the beginning of the second set, with both holding to love or 15 until the seventh game.
At 3-3, Zverev pounced to take a 40-0 lead and he broke Rune with a powerful inside-out forehand that set him up to finish easily at the net.
The third seed now seemed in total control of the match and consolidated the break with a hold to love.
But the resilient Rune defied expectation by suddenly breaking Zverev when the German was serving for the match.
As the pressure mounted, both responded by upping their level and winners flew off both racquets as Rune eventually held a gripping game at 5-5, which had lasted 17 minutes.
Zverev then served out comfortably to set up a tiebreak.
Errors again crept into Rune's play and Zverev got an early mini-break, which he defended to book his spot in the final.
'Amazing' for Humbert
In the day's second semi-final, France's Humbert exchanged early breaks of serve with Khachanov as both players started nervously in front of a packed partisan crowd.
The decisive moment in the set had seemed to come when the 26-year-old Frenchman played three poor shots at 4-4 to hand Khachanov the chance to serve out the opener.
However, Humbert showed fight and forced his opponent into an error-strewn game as he levelled immediately, and the set ticked towards a tiebreak.
Humbert double-faulted when serving at 5-2 in the breaker, before dragging a backhand into the net as Khachanov wiped out the Frenchman's mini-breaks.
The 28-year-old won four consecutive points until he smashed long on his first set point, but managed to seal the tiebreak second time round when Humbert overhit.
Humbert got the break he needed in the second set to go 3-2 ahead and kept his nose in front to serve out, even hitting an ace on set point after being given a time violation.
Khachanov called for a medical time-out to receive treatment on his thigh at 3-2 in the deciding set, his movement afterwards becoming visibly very limited.
And Humbert took full advantage as he pushed the Russian back and forth across the baseline as he won four consecutive games to reach a career-first Masters final.
"It is amazing to do it in Paris at my favourite tournament. It is a dream," Humbert said.
