The third seed had come under fire for the timing and length of his toilet breaks, with Andy Murray heavily criticising him following their first-round match.
The Flushing Meadows crowd subsequently turned on the Greek and booed him during his five-set loss to the Spanish teenager, who prevailed 6-3 4-6 7-6 (2) 0-6 7-6 (5).
The crowd were again unhappy as Tsitsipas left court after losing the third set before coming back to bagel Alcaraz in the fourth – a further example of the gamesmanship he has been accused of.
Tsitsipas has labelled those “completely false” and says he has been made the villain “for no reason”.
He said: “I’m not pretending that everyone loves me. My intentions are not to be loved by everyone. Every person can choose their favourite player, pick a side. I felt that way, but I kind of have ignored it.
“Because people don’t know, that’s the thing. When people are not really in the sport and don’t know what is happening, I mean, all these accusations have been completely false.
“Then the crowd here, I guess these two things were the most intense that took place here. I was surprised in a way. I don’t really let myself take me down because I’m out there playing my game. I mean, fan support is important, but I just need to go out there and perform. It doesn’t matter at that point.
“I know all of these things have been against me for no reason. I took my toilet break as a normal athlete. Might have taken a bit longer than other athletes.
“But if there is a rule that says there’s a specific amount of time that you are allowed to take, then I would probably try and follow that protocol, that rule, and stay within the guidelines and try and follow it as much as possible.
“But I feel like people, they don’t understand. They are here for the show. They want to watch tennis. They’re very impatient, especially the new generation. They just want to get it done quick.
“For me the only thing I did is change from wet clothes to dry clothes. Apparently it’s a huge issue.”
While Tsitsipas was left defending himself, Alcaraz was basking in a “dream come true”.
The Spaniard has already been hailed as Rafael Nadal’s successor and he seized his chance on the big stage in superb fashion.
He said: “I have not words to explain how I feeling right now. I just don’t know what happened out there in the court. I can’t believe that I beat Stefanos Tsitsipas in an epic match.
“For me it’s a dream come true.”
Second seed Daniil Medvedev made serene progress into the fourth round where he will meet Briton Dan Evans.
The Russian eased past Pablo Andujar-Alba 6-0 6-4 6-3 and never looked in danger.
Diego Schwartzman, seeded 11, also had a comfortable night, motoring past Alex Molcan 6-4 6-3 6-3.