"It's amazing to be in a semifinal," she said in her post-match press conference. "But, you know, not satisfying. I want to keep going, keep playing. There's more things to do out on a tennis court that I'm hoping to achieve."
Vandeweghe might have been forgiven for having a letdown less than 48 hours after defeating World No.1 and defending champion Angelique Kerber in the previous round.
But with the help of coach Craig Kardon, it was clear the unseeded American came to play from the outset, earning break points in the very first game against Muguruza, who was playing in her first major quarterfinal since winning Roland Garros.
"I thought I took care of the things that I could control, which is the most important thing: not letting outside factors affect anything that was happening.
"It's kind of weathering the storm a little bit, knowing what Craig and I talked about before the match: the game plan is going to work, and believing in it, not wavering from it, which I'm very proud of myself for doing, especially early in the first set when I was kind of squandering quite a few break points."
The first set came down to one break of serve, which Vandeweghe converted and never looked back, losing just one more game in one hour and 23 minute masterclass.
"Maybe I play better nervous and scared. I don't know. I think I don't shy away from a challenge necessarily. I never have. Growing up, I've always just been wanting to prove people wrong in a lot of different regards.
"I think it's more that I take it as an enjoyable challenge. It's what I want to do. It's where I want to be. To face the best players is definitely an accomplishment, to say for myself that I've gotten to the point that I've beat and face these top players."
By the end of the match, she hit 31 winners to 20 unforced errors, handcuffing the typically aggressive Muguruza, holding the Spaniard to only 14 winners against 16 errors.
"I was surprised," Muguruza said after the match. "I think she played unbelievable. Three times we played in the past, she didn't show this level.
"Her serve, her shots were there. She barely missed. So it was a pretty good performance from her."
"It's a dream to play someone you grew up watching. To play an unbelievable player, future Hall of Famer in Venus, and to be on the court with her, I've only experienced it one time before.
"But to do it at this stage of a Grand Slam is kind of crazy. I mean, I can't really put it into words. Not only when I was younger, it was unknown if I even wanted to play tennis, because I was playing basketball as well, but it was kind of, like, you see that, you see it happening, but you more see yourself there. You don't see who the opponent is on the other side when you get there.
"To definitely have two Americans against each other in the semifinal I think is pretty cool."
? #AusOpen (@AustralianOpen) January 24, 2017