De Minaur breezed to a 6-3 6-2 win in just over an hour and a half in sappingly hot conditions at Homebush.
Ashleigh Barty and Alex de Minaur have shown no ill effects following their short turnaround from the Sydney International by collecting first-round triumphs at the Australian Open. "I thought that I had to be really tough today", de Minaur said.
Thompson, 24, had broken his teammate's serve early in the second set, but it was not enough to hold back the 19-year-old De Minaur.
Seppi was again the first to strike in the second set.
The up-and-coming star's straight sets victory is the ideal warm-up two days out from his first-round Australian Open clash with Portugal's Pedro Sousa. "I think they are punishing Aussies for playing deep in their home tournaments and I think that's not what they should be doing".
Boundless energy and the determination to chase down lost causes have been the cornerstones of De Minaur's early success and he was in fine form on Saturday, recovering from losing an early break to win the first set.
'And to finally be able to take that step further and get my first win, it's something that's really special in front of friends and family and in the courts I grew up'.
De Minaur is one of the few big names playing in the Sydney tournament the week before the Open, with only four of the world's top 30 playing at the event and another six playing in Auckland.
"That's pretty much all I can ask from myself".
"A lot of work, a lot of training, a lot of sacrifice goes into even making a final and to get a win, I'm speechless".
"(But) I felt good out there.
His reward is a return on Wednesday to play Mirza Basic or Henri Laaksonen for a likely third-round shootout with the great Rafael Nadal.
"I'm going to do everything in my power to come back in the final and leave it all out there".