The Serbian top seed trailed by two sets overnight after the Court One match was interrupted by rain on Friday and there was no escape for the 29-year-old as Querrey, the 28th seed, completed a huge shock.
His 6-3 7-5 6-2 Centre Court triumph over Aussie world No.57 John Millman - which was not as straightforward as the scoreline suggests - stretches Murray's incredible and consistent record at the Slams.
Asked about the court, he said: "I'm more comfortable on Centre, because I've played 90 per cent of matches there".
"My draw's still exactly the same".
Third seed Agnieszka Radwanska, the 2012 runner-up, enjoyed a 6-3, 6-1 win over Katerina Siniakova and next plays Dominika Cibulkova, the 19th seed from Slovakia.
"The bookies don't always get it right".
"Before the tournament, (it) was to win one match on grass. That's what I'll try and do".
Djokovic had two more chances to break in the fifth game before finally breaking through at the 12th time of asking for a 5-4 lead. He made me come out and win those big points.
Djokovic summed things up best when he said: "Obviously, my best wasn't enough this year". That's natural. That's what everyone does.
"When you go indoors it slows the conditions down a bit so it wasn't easy to hit too many winners".
Following the defeat, Djokovic said that it was disappointing to lose the match, but added that it was not the first time he lost the Grand Slam encounter, Sport24 reported. "Then you get on with it".
Considering Djokovic's form, he would likely bounce back from a stunning loss same as what he did winning the Madrid Open after an unexpected defeat from Jiri Vesely in the second round of the Monte Carlo Masters. But history suggests that that's not going to happen.
"Hopefully, you know, his good vibes - he's a very happy-go-lucky guy - hopefully his positivity out there wears off on me as well and I think vice versa". "I didn't want to, but I guess I had to retire today". Given Querrey's serving prowess, it's unlikely Raonic could pull off the same kind of comeback after falling down two sets.
"But rather than it being a surprise, it should really be celebrated now, what he's actually done".
"It's an fantastic feeling to be able to hold four Grand Slams at the same time".
They played the first three sets at No. 2 Court on Saturday before play was suspended because of darkness.
Querrey puts a lot of his new-found confidence down to working with US Tennis Association coach Craig Boynton, who got to his man during every rain delay to keep him thinking positive.
Still the roof was not closed, and that decision was made to look extremely misguided when two points after they resumed the rain came down again.
And then there's Murray.
Raonic broke Querrey three times, including in the final game to end the contest.
Play is underway on Day 7 at Wimbledon, only the fourth time in the tournament's 139-year history that matches are being played on the middle Sunday.
"It's been a little bit tricky". Makes it a bit stop-starty. But he did say that it was the same for both players, which I was glad about.
Murray has consistently said he will be in Belgrade for the tie on clay as long as he is healthy. I have seen him beat Novak before. "I'm still here and I'm playing my match tomorrow". "If I'm physically fit, I'll be there".