Keys was bundled out 4-6, 6-1, 6-1 by fellow American Shelby Rogers, who grew up in Charleston.
Keys was bundled out 4-6, 6-1, 6-1 by fellow American Shelby Rogers, who grew up in Charleston and delighted her home crowd with an aggressive performance that overwhelmed her compatriot.
"It's really hard to explain," Rogers said in an on-court interview. "I've played here so many years in a row, and it's not always easy.
"I feel like I've learned a lot of lessons and I've grown up right here in front of this crowd. It's so special," the 24-year-old added.
Rogers will face Naomi Osaka in the next round after the Japanese player knocked out number 13 seed Zhang Shuai 6-4, 6-4 earlier in the day.
Elsewhere, Venus Williams was left baffled after losing a punishing three-set, second-round battle to Germany's Laura Siegemund.
The veteran third seed bowed out in her opening match of the tournament, losing 6-4, 6-7 (3/7), 7-5 to the 29-year-old world number 37.
It was Siegemund's second three-setter of the tournament, and the German admitted she was as surprised as anyone following a win in which she saved two match points.
"I have no idea!" Siegemund told an interviewer when asked to explain her victory.
"It was a really good match; it was going up and down. I just tried to believe in my game, and if I was down, I told myself I was going to get more chances."
Siegemund squandered a match point in the second set and was then broken as she served for the match in the same set as Williams forced a third set.
Siegemund then recovered twice from breaks in the decider and saved two match points of her own as Williams served for the match at 5-4.
Siegemund broke however to level it at 5-5 and then held and broke Williams to clinch victory.
Williams admitted she had been unable to shake off Siegemund.
"I tried my best to think this could be the best match she'll ever play in her life, honestly," Williams said. "I basically won but still lost.
"I really played the best game I could. I pretty much hit winners, but she hit winners back on me, and I just didn't have any answers for that."