The world number one saw a run of 22 consecutive wins ended by Karen Khachanov in the Paris Masters final, but he swiftly rediscovered his rampant form of the past few months at the season-ending tournament.
In front of a thrilled London crowd including Juventus star Cristiano Ronaldo, Djokovic went after Isner from the off and there never appeared an opportunity for the underdog to truly trouble the top seed.
Indeed, Djokovic ruthlessly wrapped up yet another triumph in straight sets, making a superb start to the competition that he has won five times previously.
Djokovic drew first blood as a double fault from Isner, renowned for his serving quality, gifted away two break points, the first duly taken with a clinical cross-court return.
The Serbian pushed for a further break, repeatedly finding gaps through which to punish Isner, but a series of aces kept the 14-time grand slam champion at bay.
A hold to love saw Djokovic take the opener, though, and he continued to match Isner stride for stride even when the world number 10 held confidently at the start of the second to give himself a platform to kick on from.
One loose Isner drop shot saw Djokovic haring across the court to win the point and gee up the crowd en-route to the crucial breakthrough, achieved as his opponent hammered into the net.
Djokovic then proved an immovable object as the usually unstoppable serves rained in and he took a third match point with a marvellous fading backhand, leaving Isner bemused at the end of a contest in which he performed well and was still blown away.