The world number one clinched her 17th major title at Flushing Meadows 12 months ago, defeating Victoria Azarenka in three sets.
That represented Williams' second successive US Open crown - her fifth overall - and the 32-year-old will begin her bid for a hat-trick of consecutive wins against world number 103 Townsend.
"I am just going to do the best I can, have fun and see where I land," Williams said in the immediate aftermath of Thursday's draw.
Should Williams progress as far as the quarter-finals, she could face eighth seed Ana Ivanovic, who will take on Alison Riske in her first-round match.
Second seed Simona Halep was runner-up to Maria Sharapova at the French Open earlier this year, and the pair will be on for a repeat meeting in the last eight should they come through respective opening clashes against Danielle Rose Collins and Maria Kirilenko.
Petra Kvitova, crowned Wimbledon champion last month, takes on Kristina Mladenovic first up, and the Czech could face rising star Eugenie Bouchard - whom she beat in the final at the All England Tennis Club - in the quarter-finals.
Bouchard begins against world number 120 Olga Govortsova while elsewhere, fourth seed Agnieszka Radwanska will start her campaign against Canada's Sharon Fichman.