Djokovic's bid for an 18th grand slam title came to an end after he was disqualified at Flushing Meadows.
The Serbian's stunning exit has opened up the men's draw, with a first-time grand slam winner set to be crowned in New York.
Zverev and Shapovalov remain in contention for their maiden major triumphs after impressive wins.
ZVEREV, SHAPOVALOV INTO LAST EIGHT
Zverev, the German fifth seed, needed just one hour, 34 minutes to crush Spaniard Alejandro Davidovich Fokina 6-2 6-2 6-1.
The 23-year-old Zverev progressed to his fourth grand slam quarter-final and first at the US Open after the comfortable win.
He hit 39 winners and 22 unforced errors in a straightforward victory.
Shapovalov, 21, also progressed thanks to a hard-fought 6-7 (0-7) 6-3 6-4 6-3 win over David Goffin.
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The Canadian 12th seed needed three and a half hours and 51 winners to reach a grand slam quarter-final for the first time.
Shapovalov became the first Canadian man to reach the quarter-finals at the US Open in the Open Era.
Before Sunday, Shapovalov would have been expecting to face Djokovic in the last eight before the drama on Arthur Ashe Stadium.
The favourite to win the major, Djokovic was defaulted during his fourth-round clash with Pablo Carreno Busta.
Djokovic had just been broken to fall 6-5 behind in the first set when he hit a ball that struck a linesperson, leading to his disqualification.
The three-time US Open winner later posted an apology on social media as he bowed out in extraordinary circumstances.
"This whole situation has left me really sad and empty. I checked on the linesperson and the tournament told me that thank God she is feeling ok," Djokovic wrote. "I'm extremely sorry to have caused her such stress. So unintended. So wrong. I'm not disclosing her name to respect her privacy.
This whole situation has left me really sad and empty. I checked on the lines person and the tournament told me that thank God she is feeling ok. I‘m extremely sorry to have caused her such stress. So unintended. So wrong. I’m not disclosing her name to respect her privacy. As for the disqualification, I need to go back within and work on my disappointment and turn this all into a lesson for my growth and evolution as a player and human being. I apologize to the @usopen tournament and everyone associated for my behavior. I’m very grateful to my team and family for being my rock support, and my fans for always being there with me. Thank you and I’m so sorry. Cela ova situacija me ÄÂini zaista tuÅ¾nim i praznim. Proverio sam kako se oseÄÂa linijski sudija, i prema informacijama koje sam dobio, oseÄÂa se dobro, hvala Bogu. Njeno ime ne mogu da otkrijem zbog oÄÂuvanja njene privatnosti. Jako mi je Å¾ao što sam joj naneo takav stres. Nije bilo namerno. Bilo je pogrešno. Å½elim da ovo neprijatno iskustvo, diskvalifikaciju sa turnira, pretvorim u vaÅ¾nu Å¾ivotnu lekciju, kako bih nastavio da rastem i razvijam se kao ÄÂovek, ali i teniser. Izvinjavam se organizatorima US Opena. Veoma sam zahvalan svom timu i porodici što mi pruÅ¾aju snaÅ¾nu podršku, kao i mojim navijaÄÂima jer su uvek uz mene. Hvala vam i Å¾ao mi je. Bio je ovo teÅ¾ak dan za sve.
A post shared by Novak Djokovic (@djokernole) on Sep 6, 2020 at 3:58pm PDT
"As for the disqualification, I need to go back within and work on my disappointment and turn this all into a lesson for my growth and evolution as a player and human being.
"I apologise to the @usopen tournament and everyone associated for my behaviour. I'm very grateful to my team and family for being my rock support, and my fans for always being there with me. Thank you and I'm so sorry."
CORIC INTO FIRST QUARTER-FINAL
Borna Coric backed up his incredible win over Stefanos Tsitsipas by easing past Australian Jordan Thompson 7-5 6-1 6-3.
The Croatian 27th seed was too good for Thompson on his way to a first major quarter-final, where Zverev awaits.
"Look, definitely it's a very good chance for all of us. Again, like I said, I think maybe like a couple minutes ago, I need to focus on my next match and on my next opponent, which is a very, very tough opponent," Coric said afterwards.
"There's going to be new grand slam champion, for sure. Yeah, that could potentially can happen that some of us can do something more in the future. But again, it doesn't mean anything. I'm really looking forward to seeing who it's going to be. I think we all have a very good chance. Yeah, it's going to be very interesting.
"For me, the most important is just to focus on the next match, like I said at the beginning. I cannot focus on the finals or what happened earlier in the day. I just need to focus on my next match."
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