Muller won in 1hr 43min to end the Japanese player's bid for a first ATP Tour title in six years.
Comeback king Muller became just the third man to win a tour-level title having lost the opening set in every match he played during the tournament.
"Thank you everyone for the support tonight," said the Frenchman, who is projected to rise 11 places in the world rankings to a career-high 56th on Monday.
"It's been an amazing week for me, losing the first set in all the matches," he added.
"I have no words, I'm sorry, I just won the match, but thank you everyone."
Nishikori, 35, who reached the US Open final in 2014, raced through the first set at Victoria Park in just 33 minutes but ran out of steam to lose in 1hr 43min.
It was the injury-plagued Nishikori's 27th tour-level final and his first since wining in Brisbane in 2019.
The former world number four Nishikori has emerged from years of injuries, including major hip surgery, to roll back the years in a fairytale run to the Hong Kong final.
A wildcard at the tournament, he beat third-seeded Karen Khachanov, former top 10 player Cameron Norrie and Denis Shapovalov on the way to the last four.
He will return to the top 100 for the first time since June 2022 on Monday.
"I want to thank Kei, because he is an amazing player," said the 27-year-old Muller.
"I'm so happy for him that he can play without injuries, so good luck for the rest of the season."
