Earlier, unseeded Isner had blasted his way into the final with a 6-7 (5) 7-6 (9) 6-3 marathon win over Argentine Juan Martin Del Potro.
Rebounding nicely from a shock first round upset at Wimbledon, Nadal has been in sizzling form picking up his 58th career title last week in Montreal while extending his hardcourt winning streak to 14-0 with a run to the final in Cincinnati.
A win on Sunday would give the third ranked Spaniard his ninth title of the year and leave him the red-hot favourite heading into the US Open which begins on Aug. 26 in Flushing Meadows.
A contest between the towering 6-foot, 10-inch (2.06m) Isner and the 6-foot, 6-inch (1.98m) Del Potro was always going to be a bruising baseline battle and the match more than lived up to predictions as the two giants slugged it out for 2 hours and 47 minutes.
The semi-finals had a dramatically different look from what tennis fans might have hoped with the ATP Tour's 'big four;' world number one Novak Djokovic, number two Andy Murray, number three Nadal and five-time Cincinnati champion Roger Federer all featuring in the last eight.
But after a day of upsets that saw only Nadal survive, the partisan crowd still had plenty of reason to cheer as Isner carried the US flag into the semi-finals picking up his first career win in five tries against the seventh seeded Argentine.
Isner, who delivered the biggest shock of the quarter-finals toppling Djokovic, has traditionally saved his best for the home crowd with 13 of the his 15 career ATP Tour final appearances coming in the U.S. and he proved once again to be a crowd pleaser pounding 23 aces past his opponent.
Since retiring in the second round at Wimbledon with a left knee injury Isner has been in sizzling hardcourt form putting together a 15-3 match record while picking up his seventh career title in Atlanta followed by a runner-up finish in Washington.
"I've been winning a lot of matches this summer but I feel like this tournament here is where I'm really starting to put it all together," Isner told reporters.
"No offence to the other guys I've beaten prior to this but like you just said, I've beaten three top-10 guys in a row.
"I have been playing well, really in pretty much all facets of my game. There's definitely some stuff I can always improve on, but I do think I'm playing well."
In a tight opening set that failed to produce a break, it was Del Potro taking the initiative winning the tie-break 7-5.
The 2009 US Open champion had looked poised to end the contest in two sets serving for the match at 5-4 only to double-fault on match point opening the door for Isner.
The 28-year-old American seized his chance but it was not easy needing five set points before clinching the tie-break 11-9.
Isner rode that wave of momentum from his tiebreak into the third set breaking Del Potro at the first opportunity and pulling in front 3-0 on way to a hard fought win.