The Croat was stunned 3-6 1-6 6-4 7-6 (7-3) 7-5 by Argentina's world No.82 Guido Pella in three hours 12 minutes.
The 38-year-old American - last year's runner-up at Wimbledon - was the oldest entrant in the women's singles field.
Venus Williams has become the latest former champion to be knocked out at Wimbledon.
After defending champion Garbine Muguruza suffered a shock exit in the second round on Thursday, it was 10th seed Keys' turn to endure an unexpected 7-5, 5-7, 6-4 third round defeat.
In addition, this was Roger's 335th Grand Slam win and the 94th at Wimbledon, moving closer to that magical number that he could potentially reach in 2019.
The match on Monday will also be a tussle between two of the tour's mothers. She sat out Wimbledon past year while pregnant.
Isner faced two match points against Bemelmans at 5-4 in the fifth set but held and then broke in the next game.
The Jim Jordan Matter
President Trump has stood behind Jordan, telling reporters on Air Force One Thursday that he believes the congressman's denials . Strauss's inappropriate touching of athletes was open knowledge, he said, and he remembered talking about it with Mr.
Eastern Canada Heat Wave Continues, Causing Several Deaths In Montreal
Urgences-sante president Nicola D'Ulisse says the service is overwhelmed and has reached the limits of what it can provide. A blanket of steamy, hot air has gripped Quebec and much of central and eastern Canada since Saturday.
Iran Aims to Keep Oil Exports Flowing Despite US Sanctions
But those moves may be tempered by an equal desire by the U.S. and other country for stable oil prices. He added, "We will prove that the USA claim to stop exportation of Iran's oil is an illusion".
In the first point of the breaker, Buzarnescu ended a rally by plopping a forehand into the net, and after Pliskova followed up by holding her two service points for 3-0, the set was slipping away from the Romanian.
"Yesterday he was playing so, so good, and hitting the ball so hard that I couldn't do anything", the 82nd-ranked Pella said.
"Honestly, I think today was a massive mishandle of nerves", Keys said.
Ekaterina Makarova of Russian Federation also reached the fourth round, following up her victory over second-seeded Caroline Wozniacki with a 4-6, 6-4, 6-1 win over former semifinalist Lucie Safarova of the Czech Republic. "I felt my mind go and move on".
The Swiss defeated the Croat in the 2017 final at the All England Club, while he was pushed to five sets in the final of the Australian Open earlier this year. The second set went back and forth, with both players getting advantages before finally it went to a tiebreak.
The Israeli tennis star Dudi Sela was beaten Tuesday by world number one Rafael Nadal in the first round of the Wimbledon Grand Slam tournament, in his third loss to the Spaniard in three career matches.
Nick Kyrgios, seeded 15, unleashed 42 winners to see off Robin Haase of the Netherlands 6-3, 6-4, 7-5.