Harrison is considered a burgeoning talent in American tennis, but was out-classed by Djokovic in about one hour and a half, 6-1, 6-2, 6-3.
The Serbian star won the first set in just 20 minutes, and committed just 16 unforced errors in the match. Harrison, who is ranked No. 62, previously stated that it was a "good opportunity" to face Djokovic, but the hard-working youngster had his hands full with one of tennis's elite players.
"I tried to focus from the start," Djokovic said, after the match. "Obviously, I knew he had nothing to lose. He's going to come out and hit big serves. Pity for him, I don't think he played his best."
Djokovic is pursuing his third consecutive Australian Open title, and the fourth of his career. He will next face No. 31-seeded Radek Stapenek of the Czech Republic in the third round.
Stapenek, 34, dropped the first two sets of his first-round match, but has won six consecutive sets since.