The 22-year-old fourth seed proved too hot to handle on Margaret Court Arena, blazing to a 6-4, 7-5, 6-3 win to keep his record of not dropping a set during the tournament intact.
He will play either Australian Alex de Minaur, seeded 10, or fifth-seed Russian Andrey Rublev for a place in the semi-finals.
It was a sterner test this time for the Italian, who charged through his previous two matches for the loss of just 10 games, but still a comfortable win.
"He is an incredible player, I just tried to stay there mentally and physically," said Sinner.
"We have quite similar game plans... I just tried to mix up the game and I'm very happy."
Sinner had won two of the pair's previous three matches. Khachanov's sole victory came when he recovered from 0-2 down to win over five sets in the 2020 US Open first round.
Since then, Sinner has firmly established himself as a member of the sport's elite, while Khachanov has struggled against top-10 opponents.
With the wind in his sails, the Italian broke early in the first set and repelled everything the Muscovite threw at him.
The second set was a tighter affair before Sinner pounced with a forehand winner at the end of an 18-shot rally to break for 6-5 then served out to love.
The pattern was similar in the third set, with Khachanov always on the back foot and chasing the match.
