Mebanshan Suting (35th minute) scored for Meghalaya in the closing stages of the first half, while Nongrud Jefforson (46th min), Kynter Lenningston (61st min) and Kurbah Michaelson (69th min) found the net after the break.
This is the second time after 1978 that a team from Meghalaya has won the U-17 Boys' title. They had lost in the final in 2011.
Assam won in 1986 and 1992 and this was their fifth appearance in the final.
The goal seemed to lift the spirits of the Meghalaya players and they dominated the second half. Nongrud doubled the lead with a nice diving header off a cross from the left a few minutes after the restart.
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Lenningston scored the third goal with a wonderful long range effort.
An unmarked Michaelson drove the final nail in Assam's coffin, scoring with a header after being fed by Nongrud Jefferson.
The champions, OM Roy Memorial, Meghalaya will take part in the Bayern Youth Cup, a tournament organised by Adidas in association with German club Bayern Munich, to be held in the capital by the end of this year.
"It will be a great opportunity for these boys to play in the Youth Cup and the winners will play in the World Youth Cup in Germany," Tushar Goculdas, Brand Director of Adidas, said.