The Barca midfielder becomes an international centurion 11 years and three days on from his debut in a Euro 2008 qualifier against Estonia.
Speaking ahead of the match, Rakitic admitted it was fitting for him to reach the milestone against Spain, having played in La Liga since 2011.
"I remember how I could hardly wait my first appearance for Croatia," he said. "Today, 11 years later, I can hardly wait my hundredth.
"It's incredible, I'm so happy and proud, and I could not have wished a better opponent. However, it will not be a real celebration for me without team success. We have to fight."
Rakitic is the eighth Croatia player to reach 100 appearances, after Dario Simic, Vedran Corluka, Ivica Olic, Josip Simunic, Stipe Pletikosa, Luka Modric and Darijo Srna.
Srna is their most-capped player of all time on 134, but at just 30 years of age, Rakitic can harbour realistic hopes of overtaking that record in the near future.
Tonight marks the first game of Croatia's Nations league campaign, while Spain come into the match fresh off the back of a well-earned 2-1 victory against England at Wembley Stadium on Saturday night.
Goals from Saul Niguez and Rodrigo gave the visitors the three points after Marcus Rashford opened the scoring for Gareth Southgate's men.
Zlatko Dalic will be confident of his team faring slightly better against Spain, given the fact that they reached the World Cup final this summer in Russia after defeating England in the semifinals.