The 82-year-old Austrian has been front and centre of Red Bull's remarkable run in F1 since their arrival on the grid back in 2005, helping them to six constructors' championships and eight drivers' titles.
The 1971 winner of the Le Mans 24 Hours for Porsche is a close ally of Verstappen, who missed out on a fifth successive title by only two points to McLaren's Lando Norris in Abu Dhabi on Sunday.
Marko was responsible for Red Bull's young driver programme, and was behind Vettel's four titles, along with Verstappen's emergence as one of the all-time greats.
His departure comes months after Red Bull sacked team principal Christian Horner, who like Marko was at the team for its launch two decades ago.
Horner's successor, Laurent Mekies, commented: "It is very sad news that Helmut is leaving us.
"He has been such an integral part of our team and of Red Bull's entire motor racing programme for more than two decades.
"This is therefore the end of a remarkably successful chapter. His departure will leave a void, and we will truly miss him."
Marko reflected on his "extraordinary and extremely successful journey" with Red Bull.
"Narrowly missing out on the world Championship this season has moved me deeply and made it clear to me that now is the right moment for me personally to end this very long, intense, and successful chapter," he added.
"I wish the entire team continued success and am convinced that they will be fighting for both world championship titles again next year."
Red Bull's CEO of corporate projects and investments Oliver Mintzlaff said the decision to leave had been Marko's.
"Helmut approached me with the wish to end his role as motorsport advisor at the end of the year.
"I deeply regret his decision, as he has been an influential figure for more than two decades, and his departure marks the end of an extraordinary era," he said.
Mintzlaff singled out Marko's ability to spot talent via the team's junior programme.
"Names like Sebastian Vettel and Max Verstappen stand for the many drivers who were discovered, supported, and guided to the very top under his leadership.
"His passion, his courage to make clear decisions, and his ability to spot potential will remain unforgettable," he added.