Djokovic had lost just 10 games through the first two rounds and despite beating 25th-ranked Seppi in all 10 of their previous meetings, the 28-year-old Serb needed a tiring two and a half hours at Arthur Ashe Stadium to reach the Round of 16.
The world number one can be excused for lighting up in anticipation when facing an Italian opponent after registering 30 successive victories against Italians.
But the 31-year-old Seppi gave Djokovic some difficulty.
"Just hanging in there, trying to create my own pace and control the rallies," Djokovic said about dealing with the capable and aggressive game of Seppi.
"It was a tough three sets."
The world number one had not faced a single break point in his first two matches, but Seppi earned one in the third game of their third-round encounter and cashed in.
Djokovic broke right back and was on his way to victory in his easiest set of the match.
Serving for the match at 5-4 in the third set, the Serb was broken again, but Djokovic broke right back in the next game and completed his victory after fighting off two break points in the final game.
"Satisfied, but you can always do better," said Djokovic, about his victory over Seppi, who ousted Roger Federer in the third round of the Australian Open this year.
"A win is a win. He is 25 in the world for a reason."
Djokovic will next play either 14th seed David Goffin of Belgiuim or Spain's Roberto Bautista Agut.
(Editing by Mark Lamport-Stokes)
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