A victory at Flushing Meadows would move Williams level with Chris Evert and Martina Navratilova on the all-time list with 18 titles behind only Australian Margaret Court (24) and Steffi Graf (22).
"She's playing for history now and she gets uptight," said Fernandez. "She's the first person to admit it.
"The window is closing, even though she'll play, hopefully, a few more years. So each major is precious."
Williams, who will turn 33 on Sept. 26 has dutifully held the fort in recent years, waiting for reinforcements from the next generation of American tennis to arrive.
Help may finally be on the way.
After much despair about the dire state of U.S. tennis eight American women featured in the top 50 of the world rankings going into the year's final grand slam, but there is still unlikely to be any passing of the torch this year.
Williams' big sister Venus is 34 yet remains the second ranked American at number 20. Sloane Stephens is the next best placed American at 22 followed by Madison Keys at 28.
Even with Li out and Azarenka's status uncertain there is plenty of danger lurking up and down the draw.
Maria Sharapova, the 2006 U.S. Open champion, has had a steady if unspectacular buildup to Flushing Meadows while Agnieszka Radwanska will fancy her chances at a maiden grand slam.
Former world number one Caroline Wozniacki will also be eyeing her grand slam breakthrough, the Dane hitting her hard court stride with a title in Istanbul, followed by making the quarter-final in Montreal and semi-final in Cincinnati.
"It's pretty wide open (after Williams)," said Fernandez. "You have to give next nod to Sharapova because she's been there before, she's won five majors, and she's mentally so tough.
"We saw (Dominika) Cibulkova get to the finals of Australia, (Eugenie) Bouchard get to the finals of Wimbledon. Li Na's not around, so that's one less top player.
"If Serena loses, then look out. It's wide open."
(Additional reporting by Steve Ginsburg. Editing by Gene Cherry)