The two players share a victory apiece from their career head-to-head meetings, with Kyrgios winning their only battle at a Grand Slam in a five-set epic at the 2020 Australian Open.
Kyrgios, who reached his first Grand Slam final at Wimbledon in July, demonstrated his immense progress by stunning the No. 1 seed and defending champion Daniil Medvedev in four thrilling sets in Sunday's night match at Flushing Meadows.
The Australian was confident heading into the last-16 clash having beaten the World No. 1 three times in their four previous meetings, and he made that record four stars out of five after getting the better of his opponent once again in a match which lasted two hours and 53 minutes.
Kyrgios's serving and power from the baseline are always key strengths of his - 21 aces and 53 winners on the day are testament to that - but he showed his versatility by coming to the net much more frequently than usual, and with great success, too, having won 62% (29/47) of those points.
This was a clear tactic of his, which the 27-year-old revealed in his post-match interview: "Obviously I felt like I disrupted his rhythm a little bit, didn't let him kind of get comfy behind the baseline, play his style of tennis."
As ever with Kyrgios, there was a moment of madness in the third set, when he came around the net to volley a looping Medvedev shot which clearly did not have enough power to reach Kyrgios's side of the court, costing himself a break-point opportunity in the process having only recently lost the second set.
In the past, though, the World No. 18 may have beaten himself up about that mistake and melted down as a result. This version of Kyrgios feels a very different beast, however, especially if he can continue to return as well against the big-serving power of Khachanov on Tuesday.
Like his forthcoming opponent, Khachanov is enjoying his greatest ever showing at the US Open, having never previously gone beyond the third round at the final Grand Slam of the calendar year.
The 27th seed, who reached a career-high ranking of No. 8 in July 2019, defeated Montreal Masters winner Pablo Carreno Busta in a five-set epic on Sunday, with the match lasting three hours and 20 minutes in total.
The 26-year-old showed tremendous character to come back from one set down to rally and win the next two sets, before his Spanish opponent set up a decisive fifth set, which Khachanov never really looked like losing having gained control at the baseline.
Indeed, he made 32 unforced errors compared to his opponent's tally of 43 across the match, which is a surprising statistic given that Khachanov would generally be considered the more aggressive player of the two.
Having won his previous three matches against Carreno Busta, the Russian admitted "that gave me confidence from the beginning", but that will not be the case against Kyrgios, who got the better of him last time they met in his forthcoming opponent's homeland two years ago.
There were four tie-breaks in that clash, suggesting we could be set for a serve-heavy encounter. In order to keep his in-form opponent at bay, then, Khachanov will need to ensure his serving and defensive skills continue to be at the highest level once again.
Tournament so far
First round: vs. Thanasi Kokkinakis 6-3 6-4 7-6
Second Round: vs. Benjamin Bonsi 7-6 6-4 4-6 6-4
Third Round: vs. J. J. Wolff 6-4 6-2 6-3
Round of 16: vs. Daniil Medvedev 7-6 3-6 6-3 6-2
First round: vs. Denis Kudla 3-6 6-1 6-2 6-2
Second round: vs. Thiago Monteiro 6-3 6-3 5-7 6-4
Third round: vs. Jack Draper 6-3 6-4 6-5 (Retired)
Round of 16: vs. Pablo Carreno Busta 4-6 6-3 6-1 4-6 6-3
Head To Head
Cincinnati Masters (2019) - Second Round: Khachanov def. Kyrgios 6-7 7-6 6-2
Australian Open (2020) - Third Round: Kyrgios def. Khachanov 6-2 7-6 6-7 6-7 7-6
The two players share one win each from their two career meetings, although Kyrgios's carries more significance having come more recently and in a best-of-five-sets Grand Slam battle.
With six tie-breaks in eight sets across their two matches, any breaks of serve will clearly prove crucial to determining the winner of their third encounter on Tuesday.
We say: Kyrgios in four sets
Having beaten the defending champion Medvedev on Sunday, we think Kyrgios could prove to be a very tough player to stop at this year's US Open.
The Australian will have taken huge confidence from reaching his first Grand Slam final earlier this year, too, and we expect him to come good in clutch moments against Khachanov, especially with tie-breaks looking likely to occur between two powerful servers.