He won 7-5 6-3 to lift his first ATP Tour trophy of the season while snapping Tsitsipas' 10-match run of victories in the process.
Ruud also denied the Greek the chance to claim back-to-back titles after he beat the Norwegian in Monte-Carlo, but the former believes victory in Barcelona has been a "long time coming".
"Honestly, this has been worth the wait. A lot of finals that I've lost have been tough, a bit disappointing, of course," Ruud told the ATP website.
"Any time you reach a final, it's nonetheless a good week, so you can't be too hard on yourself, but this one has been a long time coming.
"I'm super happy to do it here in Barcelona in front of a packed stadium and on Rafa Nadal Court. It's special to me because I looked up to him all my childhood, came here myself as a 13-year-old boy to watch him and the others play here. It's a great feeling."
Ruud got off to a poor start as Tsitsipas earned an early break, but the Norwegian recomposed himself and sealed the opening set with a break in the 12th game before taking the upper hand in the second set to wrap up victory.
Ruud added: "It was a bit of a tricky start, got broken right away. So not the best start, but I managed to settle in and broke him back. Clutched up and broke him in the end of the first, which was huge.
"It's been two long weeks for both of us. It's obvious that at some point fatigue is going to kick in. I think we were both fit enough to play today, it's not about that, but winning the first set was huge probably for either of us."
Germany's Jan-Lennard Struff celebrates winning his first ATP Tour final, on home soil in Stuttgart. (AP PHOTO)
In Munich fourth seed Jan-Lennard Struff defeated Taylor Fritz 7-5 6-3 to claim his first career title in front of a German home crowd .
Struff saved three set points in the 10th game of the first set in chilly and rainy conditions as he reeled off five unanswered games to go a set and 2-0 up.
"Unbelievable, and to do it on home soil is just incredible," Struff said on court. "I played good tennis this week, I'm very happy. I beat good guys and I'm just unbelievably happy that I did it today.
"I waited so long. I'm 33 years old and played so long on tour. It's just an amazing feeling to do it here in Germany."
At 33 years 11 months Struff is the third oldest player to win a first title since this statistic was introduced in 1990.
Later on Sunday however, Struff lost the doubles final. Paired with Andreas Mies against Yuki Bhambri and Albano Olivetti they were beaten 7-6 (8-6) 7-6 (7-5).
with DPA
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