Giraldo started well with an early break but an argument with the chair umpire about a line call seemed to rattle the unseeded player. Shortly afterward, Giraldo failed to reach Nishikori's drop shot before hitting a costly double-fault to cede back his serve.
The fourth-seeded Nishikori went on to win eight straight games to claim the first set and take control of the match. He ended up converting five of seven break chances while Giraldo committed five double faults.
Nishikori said he hopes his maiden win on clay will carry over to upcoming tournaments and the French Open.
"This title and (my showing in) Miami helped my confidence, especially this week on clay," said Nishikori. "There are three big tournaments coming up in Madrid, Rome and Roland Garros so I hope I can do well and increase my (ranking) points. My next goal is to get to the top 10."
It was Nishikori's fifth career title on all surfaces and his second of the year.
This is the first time a non-Spaniard has won the tournament at the Real Club de Tenis since 1996. Rafael Nadal won the tournament eight times during that period.
Nishikori is coached by former French Open winner Michael Chang and Dante Bottini.
"I was good on clay when I was little," Nishikori said. "I was winning all the European juniors events. Now it's much tougher than hard courts and I was struggling a bit, but I've been playing well these past couple years so there's no fear to play on clay."