Federer or Nadal have won each of the past six major tournaments, equalling their second-longest stretch of dual dominance, their other six-slam streak came way back in 2008-09.
Nadal led by two sets plus a break early in the third, when the middle finger on his racket-wielding left hand was cramping so badly he couldn't straighten it.
Simona Halep beat Sloane Stephens 3-6, 6-4, 6-1 for her first Grand Slam title.
Del Potro is playing in the French Open semi-finals for the first time in nine years.
The 13th seeded Indo-French combination went down 6-7, 2-6 to eighth seeds Nikola Mektic of Croatia and Austria's Alexander Peya in an hour and 32 minutes.
Their matchup provides a contrast in styles: Keys is a big hitter whose serves and forehands are the keys to her success; Stephens covers every inch of the court as well as anyone.
With a 6-3, 6-2, 7-6 (4) win on Monday against up-and-coming German player Maximilian Marterer, Nadal moved into the quarterfinals and above Jimmy Connors on the all-time list of match-winners at Grand Slams.
Top-seeded Simona Halep remains on course for her elusive first major after beating 16th-seeded Elise Mertens 6-2, 6-1.
The former world number one Djokovic took two hours and 25 minutes to get into the last eight at Roland Garros for the 12th time on Sunday.
The 10th-seeded Stephens was a 6-2, 6-0 winner against No. 25 Anett Kontaveit of Estonia in 52 minutes, while No. 13 Keys beat No. 31 Mihaela Buzarnescu of Romania 6-1, 6-4 in 65 minutes.
Through 14 years and 21 matches, Serena Williams vs. Maria Sharapova has evolved into one of the most enduring and multi-faceted, if also lopsided, rivalries in women's sport.
Both Serena and Venus, who have won 14 Grand Slam doubles' titles, last won the French Open together way back in 1999.
Marco Cecchinato earned the right to face Djokovic for a spot in the semifinals at Roland Garros by eliminating the No. 8-seeded David Goffin 7-5, 4-6, 6-0, 6-3 on Sunday.
The head-to-head history is overwhelmingly in Williams' favour as the American has won 19 of 21 meetings against Sharapova, including 18 in a row.
Serena Williams will face 11th-seeded Julia Goerges of Germany in the third round of French Open.
Top-ranked Simona Halep, third-seeded Garbine Muguruza and two-time champion Maria Sharapova all powered into the French Open's third round with straight-set victories on Thursday.
Bhambri and Sharan, who had also teamed up at the inaugural Maharashtra Open, sent Raja and Martin packing with a 6-3, 5-7 and 6-4 win in the opening round of the Roland Garros.
Shapovalov registered a 7-5, 6-4, 6-2 victory over 59th-ranked John Millman of Australia in his first Grand Slam match as a seeded player at Roland Garros.
There also is a message Serena wanted to send about self-worth and feeling powerful as she returned to Grand Slam action with a first-round victory at Roland Garros on Tuesday, about nine months after giving birth to a daughter.
Argentine Trungelliti, returned home to Barcelona after losing in qualifying last week but made the dash to the French capital when Australian Nick Kyrgios pulled out of his tie against Bernard Tomic with an elbow injury.
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