The Florida-based player arrived in Cincinnati on the back of four tour-level losses to unfancied players going back to the French Open in June and was defeated 6-4, 2-6, 6-4 by Kazakh world number 34 Yulia Putintseva on Thursday.
The defeat was a big blow to her preparations for the US Open, where she will bid to retain her trophy.
"I feel like I have to work on consistency, overall," Gauff, who will drop one spot to world number three next week, told the WTA Tour after declining a press conference. "I'll probably go home and try to reset."
"Obviously, I have a lot coming up soon with the US Open, so I think just trying to reset and be ready for that."
Gauff made 50 unforced errors in the match, including nine double faults, and said it was far from her best performance.
"I made a lot of errors, especially when I was up 4-2 (in the third set). I think most of the points she won were off my errors," Gauff said.
"She's always a tricky opponent to play. She mixes up the ball, has drop shots, slices. She's someone that makes you earn the match."
Gauff was not the only big name going out, as Putintseva's compatriot and fourth seed Elena Rybakina crashed to a 3-6, 7-6, 6-4 defeat by former US Open runner-up Leylah Fernandez after squandering two match points.