Top seed Djokovic breezed past world number 156 Bobby Reynolds, a 30-year-old qualifier, 7-6 (7/2) 6-3 6-1 to reach the third round yesterday.
Reynolds was the last American man standing and his defeat under the Centre Court roof means that the for the first time since 1912 there will not be a male player from his country in the third round.
Djokovic, the 2011 champion, goes on to face either Jeremy Chardy, the French 28th seed, or German qualifier Jan-Lennard Struff.
Djokovic admitted he had been wary of Reynolds after Roger Federer and Rafael Nadal had both been shocked by opponents outside the top 100.
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"It's a Grand Slam and it's sports, the top players cannot win all the time," said the Serb.
"All the lower-ranked players have extra motivation and have nothing to lose. So I needed to be extra careful and with the roof closed, it was a little different."
Reynolds, the last of 11 US men who started in the main draw on Monday, believes the American decline is only temporary.
Defending women's champion Williams and Date-Krumm, two players with a combined age of 73, set up an intriguing clash for a last 16 place.