Guedes, 22, nutmegged Matthijs de Ligt, exchanged passes with Bernando Silva and then beat goalkeeper Jasper Cillessen with a shot from the edge of the area on the hour for his fourth international goal in 17 appearances.
Portugal had only 45 percent of possession but were more dangerous throughout as they added another trophy to the Euro 2016 title they won three years ago with a 1-0 win against hosts France, also under coach Fernando Santos.
"For the last five years, we have been an almost indestructible family who know what we are capable of doing," said Santos. "We knew we could win this match."
Although the Nations League is of far less importance, the win may have partially made up for Euro 2004 which Portugal hosted and where they were beaten in the final by Greece.
Portugal extended their unbeaten record to 10 matches since losing to Uruguay at the last World Cup. They have lost only two out of 38 competitive matches since Santos took charge just under five years ago.
The game took a while to get going but when it did, Portugal were far more threatening with Bruno Fernandes and Silva involved in almost all their best moves and Cristiano Ronaldo always lurking menacingly.
Fernandes had several efforts on goal in the first half, including one that Cillessen palmed around the post and another which curled just over the bar following some nifty footwork in the penalty area from Silva.
Ronaldo, whose hat-trick against Switzerland on Wednesday took Portugal into the final, had one effort on goal in the first half when he picked up the ball on the left, cut inside and fizzed a low shot which Cillessen did well to hold.
The Dutch -- who had one day less to recover from their semi-final than Portugal -- failed to muster a shot on target in the first half.
Portugal went straight back on the attack after halftime and forced a flurry of corners before their goalkeeper Rui Patricio finally made his first save, scrambling the ball away after a defender deflected a Memphis Depay pass towards goal.
With the volume rising at the Estadio do Dragao, Portugal broke the deadlock on the hour through Guedes although Cillessen might have expected to save the shot.
As the Dutch finally stirred, Patricio made a good save from a Depay header and defender Ruben Dias made an excellent clearance from a dangerous Daley Blind cross into the penalty area.
Portugal, though, were always a threat on the break and richly deserved the win.
"You have to be better with the ball and we were not," said Netherlands coach Ronald Koeman. "They were masters at defending when they were ahead. We should have been a bit more clever in looking for free kicks -- we were not good enough tonight."
(Reporting by Brian Homewood; Editing by Ken Ferris and Clare Fallon)
