Both top seeds played at the same time Wednesday night at the Fifth Third Tennis Championships at UK's Boone Tennis Center, but only one advanced.
Great Britain's James Ward beat former Tennessee player Rhyne Williams, 6-4, 7-5.
But unseeded Chanel Simmonds shocked Melanie Oudin, who at No. 100 had returned to the site where she won her first tournament (2008) in hopes of starting the climb back to her career high of No. 31('09).
"No one expected me to win, so I could play freely," said the South African southpaw with a huge smile afterward. "It's nice to play with no pressure."
On Thursday, Simmonds will face a collegian who knows pressure — qualifier Laureen Embree, who recently won the clinching match for Florida against Stanford in the NCAA team tournament.
Ward seemed headed for a third set, but he came back from 2-5 in the second set against the 2011 NCAA singles runner-up.
"I was a little upset with the officiating, but that gave me more motivation," he said. "I was just down a break, so I told myself to hold serve and since he's a little inexperienced maybe he'd lose focus ... which is exactly what happened. That was the time to push."
Ward next faces Canada's Erik Chvojka, who advanced in straight sets over Nicholas Monroe a day after upsetting No. 8 seed Amer Delic.
Earlier, two women's seeds gave way to teenage girls in the heat of the day. No. 6 Melinda Czink of Hungary lost to 19-year-old ChiChi Scholl of Pompano Beach, Fla., 6-4, 2-6, 6-4. No. 5 Julia Cohen fell to 17-year-old Grace Min of Lawrenceville, Ga., 6-4, 6-2. Both veterans had beaten their younger opponents the last time they met.