Seeded 14 in Melbourne, Schwartzman was beaten 3-6, 4-6, 4-6 on the Rod Laver court following an impressive run.
Going into the Djokovic match, the Argentina Davis Cup star did not lose a set throughout the tournament, building on his first-round with victories over Alejandro Davidovich Fokina and Lajović and Dusan Lajovic.
Camila Giorgi of Italy produced a battling performance in round three of the Ladies Singles before succumbing to seventh seed Angela Kerber of Germany.
Giorgi of Italy lost the first set 2-6 before rallying to win the second set on a tie-break. But it was Kerber who found an extra gear in the deciding set which she took 6-3.
