It was world number one Nadal's 55th career clay-court title while he also extended his winning streak on the surface to 46 consecutive sets.
The 31-year-old Spaniard won his 11th Monte Carlo Masters last weekend also without dropping a set.
Sunday's victory reinforced his status as the overwhelming favourite to lift the French Open for an 11th time in June.
Nadal now has 77 titles overall while his career clay-court match record stands at 401 wins against just 35 defeats.
His win on Sunday was greeted by ticker-tape and a video review of all his titles on the centre court in Barcelona which now bears his name.
“It's really emotional to see that video. I never dreamed of having a career like this,” said the 16-time Grand Slam title winner.
“Last year, they made a video of my 10 titles here. Now they have had to make another video for 11 — it makes me feel like I am ageing.
“Thanks to everyone for making the tournament so special and thanks to my family who have been with me even when things have not been so smooth.”
— Rafa Nadal (@RafaelNadal) April 29, 2018
Tsitsipas, 19 years old and ranked 63, was the first Greek man to make an ATP final since Nicholas Kalogeropoulos in Des Moines back in 1973.
He was also the youngest Barcelona finalist since Nadal in 2005.
“Stefanos, you had an incredible week. You have a great future and I wish you great success,” added Nadal of an opponent who will become just the second teenager in the world top 50 next week after Canada's Denis Shapovalov.
Nadal needed just 77 minutes to claim victory on Sunday. After racing through the opening set, he was quickly 3-0 up in the second before Tsitsipas carved out a degree of hope in the fourth game when he had two break points.
They were quickly saved by Nadal who then claimed the title on a third match point in the seventh game when the teenager dumped a one-handed backhand into the net.