Murray, who seized the No. 1 spot in the rankings on Saturday for the first time in his career, secured his eighth ATP Tour title of the season and 43rd of his career by dispatching Isner in two hours and 18 minutes.
The 29-year-old Murray has won four straight tournaments in a 19-match unbeaten stretch to topple Novak Djokovic at the top of the rankings. Murray also notched a 14th ATP World Tour Masters 1000 title and joined Tim Henman (2003) and Greg Rusedski (1998) as British winners in Paris.
"This has been an incredible journey for me to get to the top of the rankings," Murray said at the trophy presentation.
Murray needed just 35 minutes to claim the first set, highlighted by a majestic half-volley winner from the baseline to keep the 6-foot-10 Isner at bay.
Isner's powerful serve proved pivotal in the tiebreak before a stifling forehand clinched the second set. The American didn't have much more in the tank, however, as Murray broke serve for the second time in the match to secure his maiden title of this tournament.
Murray improved to 8-0 in his head-to-head encounters with Isner, including a triumph in the Round of 16 at Roland Garros and two weeks ago in the Vienna quarterfinals.
The No. 1 player in Emirates ATP Race To London will turn to the final event of the 2016 season, looking to lift the trophy on home soil at the Barclays ATP World Tour Finals.
As for Isner, he finished as the top American for the fifth straight year and ended up in the Top 20 for the seventh consecutive season (No. 19).
He was unsuccessful in his bid to become the first American to win at the indoor tournament since Andre Agassi in 1999.
Isner advanced to the final aided by 18 aces in a 6-4, 6-3 victory over Marin Cilic.