De Minaur saved two match points in the last game of the fourth and, ultimately, final set but it was Tsitsipas who once again triumphed in the tiebreak to secure a win that will leave a sweet taste after a remarkable season as he was crowned the best of his contemporaries.
The pair, neither of whom qualified for the inaugural U21 event previous year, have been the most exciting breakthrough talents of 2018 and the final pitted one against the other.
Also undefeated in group play, top seed Tsitsipas claimed the win and the ATP Most Improved Player of the Year trophy.
Alex was the better player on the court, playing with aggression and keeping the points on his racquet and missing many chances to finish the match earlier.
The event does not award any ranking points, meaning Tsitsipas will remain at his current position of 15 in the world.
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"I think it would be a fantastic year-end", said Tsitsipas of winning in Milan.
'I have huge respect for him, his game and his personality. "But I know there's another star who had three wins in a row in the other part of the draw".
"I had a talk with my coach", explained de Minaur.
"Overall I'm very happy with my performance", said the player from Sydney.
'Hopefully I'm going to make the pre-season like I never did before and I can perform well next season and can compete with the top players'.
Rublev eased past Italian wild card Liam Caruana 4-3 (9-7), 4-1, 4-2 to book his passage after losing to de Minaur on Wednesday, with Munar beating American Frances Tiafoe 4-1, 4-3 (7-3), 4-1 to seal the final berth.