It was his career best eighth title this season, his 14th in Masters overall, and ended Isner’s bid for a first Masters title.
Murray, who officially replaces Novak Djokovic at the top of the rankings on Monday, now leads Isner 8-0 in their career meetings, dating back to their first match at the Australian Open six years ago.
He recently beat him 6-1, 6-3 in the quarterfinals of the Erste Bank Open in Vienna, but this was a very different match and thoroughly contested by the big-serving American.
Using 18 aces and hitting plenty of inside-out winners on his massive forehand, Isner generated considerable pressure.
But he was also erratic, wasting two break points in the seventh game of the match.
In the second set, he was 4-3 ahead and 40-0 up on Murray’s serve, but again failed to punish the Briton – last year’s runner-up to Djokovic.
But in a rare dip, Murray double-faulted during the tiebreak and Isner profited to take the set.
Isner saved break points on his first two service games of the third set, hanging on as Murray restored his superiority.
Then, serving to stay in the match, the 2.08-meter American double-faulted to trail 0-30. He won a tough first point and then hit yet another ace to make it 30-30.
Isner sank a difficult volley into the net, giving Murray a first match point. With Isner on second serve, Murray dominated a brief rally, pinging a pass down the line that Isner patted into the net with the ball close to his body.
It was a hard-fought victory and the valiant Isner stood with his head down at the net, waiting to congratulate Murray.
Murray has won four consecutive tournaments, taking his career tally to 43.
Next up is the season-ending ATP finals in London, beginning next Sunday.
He will cross the English Channel to try and take the title there, having secured his top ranking here.
Watch Paris Masters final encore on Tennis Channel