Federer's big concern would be against del Potro in the quarters.
Chris O'Neil was the last victor back in 1978, while Wendy Turnbull's runner-up finish two years later represents the last time an Australian woman reached the final at Melbourne Park.
Seeded down in 14th after not playing competitively since Wimbledon, six-time Australian Open champion Novak Djokovic is up against Donald Young.
A year ago was dominated by the Federer and Nadal who shared the spoils by winning two Grand Slams each with Federer being the reigning Australian Open Champion. He is likely to face fifth seed Dominic Thiem as early as in the fourth round.
Federer won the 2017 Australian Open.More news: China's US Debt Holdings May Be an Ace Card in Trade Dispute
Serena Williams will not defend the women's title having had her first child previous year but 2008 champion Maria Sharapova, who failed a drugs test at the tournament in 2016, is back unseeded after a ban and will face Germany's Tatjana Maria.
Despite many pundits, including John McEnroe, writing off Federer's Grand Slam chances, Annacone also believes his intelligence has been a crucial factor in his return to the top, with the Swiss tweaking his game to stay amongst the top stars.
Top-ranked Simona Halep opens against Australian wild card Destanee Aiava, has a potential second-round match against 2014 Wimbledon finalist Eugenie Bouchard, and is in the same half as Garbine Muruguza, the Wimbledon champion.
The American, who won the title previous year in Melbourne despite being in the early weeks of pregnancy to take her grand slam tally to 23, decided against trying to defend her title, saying she was not yet fully up to speed.
Tempestuous Australian 17th seed Nick Kyrgios, is in the same section of the draw and faces Brazil's 100th-ranked Rogerio Dutra Silva.More news: Supreme Court will weigh letting states collect tax on e-commerce sales
British number one Johanna Konta, seeded ninth for the first grand slam of the year, will take on Madison Brengle of the US while last year's runner up Venus Williams has been drawn against Belinda Bencic of Switzerland.
Third-seeded Muguruza is in a hard quarter containing former Australian Open champions Maria Sharapova and Angelique Kerber, and U.S. Open finalist Madison Keys. Those players are on the bottom half with second-seeded Caroline Wozniacki, who is ranked inside the top two for the first time since 2012.
Organizers defended the decision to invite Sharapova to appear as the representative for the women's draw, with tournament director Craig Tiley saying the sanction was over and the 30-year-old Russian was there as a former champion.
"The drive, I still have it. I expect to continue to do so".More news: Listen to Carrie Underwood and Ludacris' Unholy Super Bowl Anthem "The Champion"