Nadal continued his quest for a fourth US Open title by outclassing Vasek Pospisil in a straight-sets victory on Wednesday and so far his game has looked in excellent shape at Flushing Meadows.
The Spaniard has won all four previous encounters with Khachanov and has never dropped a set against the Russian so he will be confident of continuing his progress with another straightforward victory.
Nadal has defended the court extremely well in his first two matches and his court coverage will be key for him here as he will need to counter Khachanov's powerful forehands.
The young Russian has been impressive in New York so far having seen off both Albert Ramos Vinolas and Lorenzo Sonego in straight sets to reach the third round at the US Open for the first time in his career.
Facing the reigning champion is a daunting task though, and a huge step up in quality for Khachanov. He has lost to Nadal twice already this year although their most recent encounter at the Canadian Open earlier this month was a competitive affair.
His run to the semi-finals of that event represents his best performance in the Masters 1000 series and it has taken him to a career high of 26 in the world, so his confidence is good going into this meeting with the world number one.
Nadal has certainly had Khachanov's number in previous meetings but the talented Russian is improving all the time and he did cause Nadal some problems in their recent meeting in Canada. Grand Slam tennis is a different kettle of fish though and the reigning champion has the experience to navigate tough matches such as this in the early stages.
Khachanov will need to throw everything at Nadal but the Spaniard's defence has been as impregnable as ever this week, and he is likely to survive the onslaught and come through in three or four sets.