Djokovic not only lost to Querrey at Wimbledon last year but crashed out in round two here to wildcard Denis Istomin, leaving Murray in pole position to clinch his first Melbourne title.
The Scot’s response was a masterclass in counter-punch tennis as the big-hitting Querrey was taken apart 6-4 6-2 6-4 in one minute shy of two hours.
Murray will now face Germany’s world number 50 Mischa Zverev, who is into the last 16 at a major tournament for the first time after beating Tunisian Malek Jaziri.
This is familiar territory, however, for Murray, who has now reached 24 consecutive grand slam fourth rounds and, despite a late wobble, he looks well-placed heading into the second week.
He is yet to drop a set so far and there was also little evidence of his sore right ankle - rolled in the second round against Andrey Rublev - causing him any real trouble.
Instead, Murray neutralised Querrey’s booming serve, which delivered only five aces and was broken five times, while displaying a level of craft and precision the American was simply unable to match.
“It was tough,” Murray said on court afterwards. “Especially in the first set, Sam was hitting a huge ball, he served extremely well but the key moment came at 3-4 in the first set.
“I saved a break point and broke the next game and had the momentum after that.”
On his ankle, Murray added: “I felt better and better as the match went on in terms of movement.
“I was a bit hesitant at the beginning, a bit sore, but was moving well at the end so that was very positive.”
There was a degree of surprise that Murray, the top seed and world number one, was placed out on Hisense Arena, Melbourne Park’s third premier show court, but he appeared unconcerned.
“It was packed from the first ball and we love that as players,” Murray said. “It makes for a great atmosphere. I really enjoyed being back here again on Hisense.”
Djokovic’s defeat less than 24 hours previous still loomed, quite literally, as an advert featuring the Serb played out on the stadium’s big screen before the match started and between changes of ends.
But if there was ever a need to explain why it is Murray who is currently the finest player on the planet, the first set offered a decent demonstration.
He seemed to wince at 2-2 when running right to retrieve a volley, perhaps suggesting the ankle is not completely healed, and it was not plain sailing in-court either as he had to save a Querrey break point at 4-3.
But at 4-4, after eight games of scrapping and scrambling, Murray turned the screw. There were three forehands, one dipping into Querrey’s feet, the next whipped cross-court for a winner and the last fired down the line for a pass.
There was another pass, this time a backhand, again down the line, and then a superb show of defence as he scooped back two Querrey smashes until the American, impatient, belted long.
Finally, defending his third break point, Querrey submitted, rushing the net only to watch Murray flick a trademark forehand lob over his head and into the opposite corner.
It proved the decisive moment of the set, and the match, as Murray, with the sun in his eyes, served out.
After throwing everything at Murray and coming up short, Querrey looked demoralised and an error-strewn game early in the second handed Murray another break and a 2-1 lead.
A cruel net cord rubbed salt into the wounds as Murray broke again and moved two sets clear.
Murray grew unnecessarily frustrated in the third as he complained about “feeling flat” and yelled in anger after Querrey broke back to level.
But again he stepped up when it mattered, sprinting to chase down a drop shot before Querrey somehow dumped the volley in the net with the entire court at his mercy.
Murray did not waver, a bending serve down the middle confirming a straightforward victory.