Nishikori, the 2013 champion and top seed, needed 90 minutes to make his first successful title defence, picking up a $103,100 cheque in the process.
"It's amazing actually first time to defend a title and especially here," Nishikori said. "I had a great memory last year, playing great, and today was perfect.
"I think I started well. There was a couple matches before (when) I was kind of slow starting. Today was different, and it wasn't easy because he had a lot of aces... not many chances to break.
"I had to stay calm and stay focused to the end of the last tie-break. Yeah, I was really happy to defend (the title)."
Karlovic, who at 6'11" is a full 13 inches taller than Nishikori, had beaten the Japanese world number 16 in both of their previous encounters.
But, despite serving 20 aces, the Croatian could not stay with world number 16 Nishikori, who saved both of the break points he faced and was able to dominate on his own serve with an 86% first-serve point win.
"He returned really well," Karlovic said. "I was not hitting as wide as I usually can, but he was really fast.
"He was returning well, and then he won. He was a little bit better."