Khachanov's powerful serve dictated the match, as it has done all tournament. He fired in six aces and wrapped up the win in 55 minutes.
The 22-year-old Russian was only broken once all week and faced a single break point against Mannarino, which he saved.
"I'm happy with the game I displayed at this tournament, and that I was getting better and better with each match," Khachanov said. "That's what the top players do and it's what brings you results."
Khachanov has won all three of his tour finals to date, including a win in Marseille in February, while Mannarino has lost all six of the finals he has played.
Victory means Khachanov is guaranteed to enter the top 20 in the rankings for the first time, surpassing Daniil Medvedev as the top-ranked Russian.
Khachanov is the first Russian man to win the Kremlin Cup since Mikhail Youzhny in 2009.
"It was my childhood dream to win my home tournament here in Moscow," Khachanov said.