Djokovic was not able to defend his Australian Open title because he was unvaccinated and deported.
Djokovic was allowed to enter the United Arab Emirates and he won a tournament that he had won five times.
Musetti beat Djokovic in two sets at the French Open last season, but the Italian wildcard couldn't convert many break opportunities on a humid Dubai evening. He was trailing 3-1 in one set and 4-2 the second.
Djokovic stated on court that he was satisfied with his tennis after having not played for more than two and a quarter months. "Of course, there were moments when I played great, there were moments when I made a couple of unforced errors in a row uncharacteristically. It's normal to expect this (in my) first match after some time."
Next, he will face Alex de Minaur or Karen Khachanov.
Andy Murray won his first Dubai match since 2017. After nearly three hours, he beat Australian qualifier Christopher O'Connell 7-6, 6-3, 7-5