Games went on serve for the entire first set, in an intense battle between the two 1.98m giants.
The 29-year-old Del Potro produced his usual mix of power and precision from the baseline and also managed some exquisite volleys at the net.
He also got better as the set went on, and stepped up a level in the tiebreak.
He carried his momentum into the second set, breaking the Russian in the second game to sprint to a 3-0 lead.
Khachanov tried everything to come back but couldnt make inroads on Del Potro's serve and the former US Open champion closed out the match in 93 minutes.
Ferrer continues fairytale surge
The ASB Classic's final could come early after four-time champion David Ferrer continued his farewell march.
Playing in Auckland for the 13th time since 2003, Ferrer oust adopted Korean crowd favourite Hyeon Chung 6-3 6-2 in 75 minutes to set up a potential headline semifinal with Juan Martin del Potro, who plays later tonight.
Ferrer, the seventh seed, lost his first round match in three sets to Dutch veteran Robin Haase here last year but the 35-year-old has quickly found his groove this time.
Now the world No 37 and playing probably his swansong from this tournament, Ferrer has been in vintage touch this week. He has adopted an attacking mindset, getting on top of the ball and driving through his shots.
Chung had his chances – break point at 5-3 in the first set – but couldn't convert the same way he did to grind down big serving American John Isner last night.
Bautista Agut advances to semi finals
Spanish fifth seed Roberto Bautista Agut made light work of Jiri Vesely to advance to the ASB Classic semifinals with a 6-4 6-4 victory.
Bautista Agut has enjoyed a relatively easy ride, knocking over Kiwi Michael Venus and American Steve Johnson, both in straight sets, before disposing of Vesely, the 2015 champion.
World No 21 Bautista Agut won the title here in 2016 and this is his sixth visit to Auckland.
Haase stopped unheralded German Peter Gojowczyk in his tracks with a comfortable 6-4 6-4 victory to set up a semifinal showdown with Roberto Bautista Agut.
Gojowczyk knocked out defending American champion Jack Sock on Wednesday but couldn't muster the same accuracy against Haase.
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Ubiquitous Ferrer just keeps on keeping on
Defending ASB Classic champion lacks heart in defeat
The most anticipated match of the day session will see four time winner David Ferrer take on popular Korean Hyeon Chung, who upset number four seed John Isner on Wednesday night.
In the evening session Juan Martin del Potro, back in Auckland for the first time since his 2009 title win, will face 1.98m Russian Karen Khachanov.
The 29-year-old Argentine will return to the top 10 for the first time since 2014 when the latest rankings are released next week.
The final match of the night session sees Kiwi Michael Venus in the quarter final of the doubles.