Karlovic's serve, which arrows out of the ether from his giant 2.11 metre frame, is one of tennis's most terrifying weapons, but it was not enough to stop the third seed moving on comfortably with a 7-6(7) 6-4 5-7 6-4 victory.
Modern grasscourt tennis these days requires so much more than just a fearsome opening delivery, and Murray, who has now reached the last eight for the eighth consecutive year, is one of the game's most skilled returners.
Although he did drop a set, he never looked truly troubled by the Croat, whose all-round skill set is lacking in some key departments.
Karlovic was hardly an unknown quantity for Murray.
At 36, he has been around a while and is the oldest player to reach the last 16 at a grand slam since a 39-year-old Jimmy Connors did it at the U.S. Open 24 years ago.
The pair had also met five times previously with Murray winning every one, which included a skirmish at Wimbledon three years ago.
Yet knowing what to expect when facing Karlovic, does not make him any easier to master.
"It was an incredibly difficult match, it was mentally tiring because you just have to be ready when the chances come," Murray said having teed up a clash with Canada's Vasek Pospisil.
The towering Croat fired down 29 aces, which by his standards was a poor return given he had walloped 136 in his first three matches.
From the start, he was launching 130mph missiles, but Murray's keen eye was picking them up in the afternoon sun, and the Briton moved quickly into a two-set lead.
However, a cat-and-mouse third set was decided when Karlovic broke in the 12th game, dampening the glee of the locals on Centre Court but injecting some much-needed life into the match.
With his enthusiasm rekindled, Karlovic then dug in, holding serve comfortably until Murray sniffed his chance and broke for a 4-3 lead in the fourth.
After passing up a chance to break back, Karlovic was swiftly facing match points, saving one on his own serve before Murray closed it out in the following game as the Croat swiped a forehand long.
(Reporting by Toby Davis; editing by Ken Ferris)
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