Del Potro finished the match with his eighth ace and made only four unforced errors in securing his 18th career title and first in Sydney. He lost only six points on his serve, and Tomic appeared dispirited after being broken to fall behind 4-1 in the second set.
And it's about to get more difficult for Tomic. His next match is against top-seeded Rafael Nadal in the first round of the Australian Open. Del Potro will also play his first-round match Tuesday - against a qualifier.
Isner, ranked No. 14, won his eighth career singles title and took the title in New Zealand for the second time after his victory in 2010.
The third-seeded Isner, playing with a right ankle injury he picked up at the Hopman Cup the previous week, took a crucial minibreak to open the first set tiebreaker. In the second tiebreaker, he rallied from 3-0 down and closed with an ace on his third championship point.
"This match was very tight as every match I've played this week was very tight," Isner said. "I needed every bit of it to come out on top."
Isner heads into the Australian Open with a question mark hanging over his fitness because of his injured ankle. He has drawn a qualifier in the first round.
Nishikori, seeded No. 16 at the Australian Open, was watched in the stands by Chang, a former French Open champion and a three-time winner at the Melbourne venue in 1995-97.
Nishikori is drawn to face Australia's Marinko Matosevic in the first round of the Australian Open.
"It won't be an easy first match, and it's not easy to play an Australian," Nishikori said. "But if I can play like I did today, I have a big chance to win."
In the WTA event at Hobart, Spanish qualifier Garbine Muguruza defeated Klara Zakapalova of the Czech Republic 6-4, 6-0 to claim her first singles title.
The 20-year-old Muguzura, who did not drop a set from the qualifiers to the final, joins 2012 champion Mona Barthel as the only qualifiers to win the Hobart event.
Muguruza, ranked 58th, beat second-seeded and Wimbledon semifinalist Kirsten Flipkens in the quarterfinals, while Zakapalova defeated top-seeded and former U.S. Open champion Sam Stosur in the semis.
Muguruza won the opening set when she broke Zakapalova's service in the 10th game.
The 20-year-old Muguruza didn't play after Wimbledon last year because of right ankle surgery, and the recovery took longer than expected.
"I started to play on a chair, and then it was a little bit more until I was like normal," she said. "I didn't expect to win a lot of matches in the second tournament of the year but I just know that I'd worked so hard before. I was like a big bull."