Djokovic heads long-time rival Rafael Nadal and defending champion Roger Federer, with young-gun Alexander Zverev seeded four as he targets a maiden Grand Slam title.
Unseeded Estonian Kanepi knocked Halep out of the first round at Flushing Meadows previous year, making the Romanian the first top seed to lose at that tournament's earliest stage.
Free agent right-hander Shelby Miller signed a $2 million, one-year contract with the Texas Rangers on Wednesday and can make another $3 million in performance bonuses.
"I always have tried to remind myself that this is a dream", Federer said of his longevity at the draw ceremony held at Margaret Court Arena, where he discovered the world number 99 would be his opening opponent.
Broncos to name Vic Fangio new coach; Kubiak returning to sideline
The Broncos fired former coach Vance Joseph on December 31 after he posted 5-11 and 6-10 records in his two seasons at the helm. The gig is Fangio's first as head coach after 19 years of serving as a defensive coordinator in the NFL.
Federer's first-round test comes in the shape of Istomin, an Uzbek whom Federer has defeated in each of their six meetings, and they are in the same quarter of the draw as Andy Murray, who is unseeded and meets Spaniard Roberto Bautista Agut first up.
One of the standout matchups of the first round sees unseeded Nick Kyrgios' meet 2016 semifinalist and 16th seed Milos Raonic, with the victor of that contest going through to face either 2014 champion Stan Wawrinka or Ernests Gulbis. If it would happen defending this title, I would gladly accept it. Halep has drawn another first-round against Kaia Kanepi, who beat her at the same stage at last year's U.S. Open, and a possible third rounder against unseeded Venus Williams.
Serena Williams will face Tatjana Maria in the first round, and could meet either Genie Bouchard or Peng Shaui in the second round. "I'm just enjoying every minute of it". The 26-year-old has achieved a career breakthrough last season as she qualified for two straight semifinals in Wuhan and China Open.
British number two Heather Watson takes on 31st seed Petra Martic from Croatia while Katie Boulter, playing in her first slam main draw outside of Wimbledon, meets experienced Russian Ekaterina Makarova.